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Information on EC 7.2.2.9 - P-type Cu2+ transporter
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7.2.2.9 P-type Cu2+ transporterIUBMB Comments
A P-type ATPase that undergoes covalent phosphorylation during the transport cycle. The enzyme from the termophilic archaeon Archaeoglobus fulgidus is involved in copper extrusion from the cell [1,2].
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Word Map
- 7.2.2.9
-
3.6.1.3
- ceruloplasmin
- cisplatin
- atpases
-
copper-dependent
-
x-linked
- na+
- platinum
- triphosphatase
-
trans-golgi
-
metal-binding
- biliary
- overload
-
copper-binding
-
disease-causing
- metallothioneins
-
k+-atpase
- oxaliplatin
- ouabain
-
copper-induced
- carboplatin
-
platinum-based
- mg2+-atpase
-
toxicosis
-
occipital
-
kayser-fleischer
- copa
- adenosinetriphosphatase
- na+,k+-atpase
- phosphoenzyme
- d-penicillamine
-
cisplatin-resistant
- ferroxidase
-
mottled
-
long-evans
-
copper-containing
-
copperi
- tetrathiomolybdate
-
copper-deficient
-
metallochaperone
-
kinky
- cinnamon
-
k+-stimulated
-
cddp-resistant
-
multicopper
- bathocuproine
- medicine
-
cu-induced
- drug development
-
3.1.3.5
-
terrier
-
k+-dependent
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
atp7b, atp7a, copper transporter, copper-transporting atpase, copper-transporting p-type atpase, menkes protein, cu-atpase, copper transporting p-type atpase, wilson disease protein, copper atpase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
adenosine 5'-triphosphatase
-
-
-
-
ATP hydrolase
-
-
-
-
ATP phosphohydrolase
-
-
-
-
ATP7A
ATP7B
ATPase
-
-
-
-
BcCCC2
Ccc2
CcoI
complex V
-
-
-
-
CopA
CopB
copper ATPase
copper transporter
copper transporting ATPase
copper transporting P-type ATPase
copper-ATPase
copper-translocating P-type ATPase
copper-translocating P1B-type ATPase
copper-transporting ATPase
copper-transporting P-type ATPase
CtpA
Cu(I)-ATPase
Cu-ATPase
Cu-translocating P-type ATPase
Cu-transporting P-type ATPase
Cu2+-ATPase
CUA-1 ATPase
-
-
-
-
CuTP
EC 3.6.1.3
-
-
related
-
EC 3.6.3.4
-
-
formerly
-
GolT
Menkes copper-transporting ATPase
Menkes disease protein
Menkes disease-associated protein
-
-
-
-
Menkes disease-associated protein homolog
-
-
-
-
Menkes P-type ATPase
-
-
-
-
Menkes protein
MNK
moe
HMA5 belongs to a large family of genes encoding P1B-type cation-transporting ATPases
PAA1
PcpA
Pinal night-specific ATPase
-
-
-
-
WCBD
-
-
-
-
Wilson copper-transporting P-type ATPase
-
-
-
-
Wilson disease copper-transporting ATPase
Wilson disease protein
Wilson disease-associated protein
-
-
-
-
Wilson disease-associated protein homolog
-
-
-
-
Wilson protein
additional information
ATP7A
-
-
ATP7A
-
ATP7B
-
-
-
-
ATP7B
-
-
ATP7B
-
CopB
the enzyme is a member of the P1B-3-subgroup with a Cys-Pro-His sequence in H6 and 17 His residues within the first 51 amino acids
Cu2+-ATPase
-
-
-
-
MNK
-
-
-
-
Wilson disease copper-transporting ATPase
-
-
-
-
Wilson disease protein
-
-
-
-
additional information
-
ATP7A and ATP7B are members of the P1B-subfamily of the P-type ATPases
additional information
-
ATP7A and ATP7B are members of the P1B-subfamily of the P-type ATPases
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + H2O + Cu2+[side 1] = ADP + phosphate + Cu2+[side 2]
-
-
-
-
ATP + H2O + Cu2+[side 1] = ADP + phosphate + Cu2+[side 2]
the N-domain can not hydrolyse ATP
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
transmembrane transport
hydrolysis of phosphoric ester
-
-
-
-
hydrolysis of phosphoric ester
-
-
transmembrane transport
-
-
-
-
transmembrane transport
-
-
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SYSTEMATIC NAME
IUBMB Comments
ATP phosphohydrolase (P-type, Cu2+-exporting)
A P-type ATPase that undergoes covalent phosphorylation during the transport cycle. The enzyme from the termophilic archaeon Archaeoglobus fulgidus is involved in copper extrusion from the cell [1,2].
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CAS REGISTRY NUMBER
COMMENTARY
9000-83-3
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + H2O + Cu+/in
ADP + phosphate + Cu+/out
Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake. Wilson protein domain 4 and domain 2 are two acceptors of Cu(I) from the cytosolic metallochaperone HAH1, which then somehow route copper to Wilson protein domain 5 and 6, before the ATP-driven transport of copper across the vesicular membrane
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
cloning, expression and structural characterization of copper-transporting ATPase CtrA2
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
cloning, expression and structural characterization of copper-transporting ATPase CtrA3
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper stimulates both trafficking and phosphorylation of ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
neuronal and copper-inducible expression of DmATP7 reporter gene, role for DmATP7 in export of copper from midgut cells and for copper transport in neuronal tissues
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
-
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
-
-
-
r
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper bound to the domain exists in the +1 oxidation state, upon binding, Cu(II) atoms are reduced to Cu(I) by some mechanism, binding of copper by the domain is cooperative in nature
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
each binding site ligates copper in the +1 oxidation state using two cysteine side chains with distorted linear geometry, both secondary and tertiary changes take place upon copper binding
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the metal binding domain from the Wilson disease copper transporting P-type ATPase is able to bind a variety of transition metals with varying affinities
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
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Cu-ATPase in the blood-brain barrier controls the penetration of Cu into the brain, lesions to the Cu-ATPase in cerebrovascular endothelial cells are a primary cause of low brain Cu levels in Menkes disease
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?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B translocates copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes. Disturbed incorporation of copper into the late endosomal lumen from the cytosol by the mutated ATP7B is the main defect of Wilson's disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper-translocating activity of MNK and its copper-induced relocalization to the plasma membrane represent a well coordiated copper homeostasis system. Mutations in MNK which alter either its catalytic activity or/and ability to traffick can be the cause of Menkes disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
relocalization of the enzyme is a physiological process, which may be mediated by copper levels in the breast or by hormones and other events taking place during lactation
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
autosomal recessive Wilson disease is characterized by copper toxicity believed to result from the loss of ability to export copper from liver to bile and incorporate copper into ceruloplasmin in the liver. Mechanism of alternative splicing serves to regulate the amount of functional Wilson disease protein produced in brain, kidney and placenta
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?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
responsible for ligating the copper atoms prior to transport across the membrane
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?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the gene Mc1 is responsible for Menkes disease, an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood
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?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
Cu2+ may be reduced to Cu+ prior to translocation
-
-
r
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7A is involved in copper loading observed during iron deficiency. Increased intestinal copper transport is of physiological relevance, as copper plays important roles in overall body iron homeostasis
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
because the Wilson protein delivers copper to the ferroxidase ceruloplasminm in the liver, it is likely that the Wilson and/or Menkes proteins provide copper to ceruloplasmin made in the retinal pigment epithelium
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7A and ATP7B are the key copper transporters that regulate copper homeostasis
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7B shown to regulate cellular efflux of cisplatin (DDP), control of sensitivity to cytotoxic effects determined
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
correspondence between the site of ATP7B action and distribution and the pathways of copper disposal by the liver
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
differential regulation of ATP7A and ATP7B by the hormones insulin and oestrogen in human placental cells
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
function and regulatory mechanisms acting on human copper-ATPases ATP7A and ATP7B
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
functional assessment of ATP7B variants analyzed, four variant amino acid positions identified as important for copper transport and as disease-causing changes
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
functions of ATP7A and ATP7B in copper transport reviewed, catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions summarized
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
involvement of ATP7A and ATP7B in transport of platinum-based antitumor agents
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
involvement of ATP7A and ATP7B in transport of platinum-based antitumor agents reviewed
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
involvement of ATP7A in multidrug resistance by compartmentalizing of drugs in the Golgi apparatus shown
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
role of ATP7B in liver analyzed, essential for delivery of copper to ceruloplasmin in the biosynthetic pathway and required for copper export into the bile
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
structural features and functional properties of ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
structural features and functional properties of ATP7A and ATP7B
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
transient delivery of the ATP7B- and copper-containing vesicles to the apical membrane analyzed
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-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7A, a copper-transporting P-type ATPase, plays an important role in Cu homeostasis and is affected in Menkes disease
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B is a copper-transporting P-type ATPase present predominantly in liver, hepatic ATPB7 loads cytoplasmic Cu2+ onto newly synthesized ceruloplasmin, the F37-E45 signal sequence is required in vivo, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B is a P1-type-ATPase with high selectivity to Cu+
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
kidney-specific regulation of ATP7B, unlike ATP7A, or hepatic ATP7B, which traffics from the TGN to export copper, renal ATP7B does not traffic and therefore is unlikely to mediate copper export. Role for renal ATP7B in intracellular copper storage
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the copper-translocating Menkes, ATP7A or MNK protein, and Wilson, ATP7B or WND protein, P-type ATPases are pivotal for copper homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as MNK in systemic Cu absorption and WND in Cu excretion. MNK and WND Cu-ATPases translocate Cu across biological membranes, MNK participates in vectorial Cu transport across the basolateral membrane and into the bloodstream. Phosphorylation events play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms, overview. MNK is responsible for direct Cu export in response to lactation, where hormonal induction by estrogen, progesterone, insulin and prolactin stimulate the expression and basolateral localization of MNK and the Cu uptake protein Ctr1 to perform a homeostatic function in the mothers tissue
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the enzyme is involved in copper transport, copper homeostasis, and in human cancer progression, overview. When the copper concentration in the hepatocyte increases, ATP7B relocates to the canalicular compartment and excretes excess copper to the bile, intestinal ATPA7 exports the absorbed copper from the enterocytes into the blood stream to supply the copper for the systemic need in a process that involves trafficking of he transporter towards the basolateral membrane. Copper is delivered by specific cytosolic chaperones. ATP7A is essential for the function of a copper-dependent enzyme tyrosinase in the secretory pathway in melanosomes
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper is transferred to ATP7A and ATP7B by ATOX1, i.e. HAH1, a cytosolic metallochaperone protein interacting via the N-terminal domain of Cu-ATPases
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
Cu+ stimulates catalytic activity of ATP7B, inducing the hydrolysis of ATP via formation of an acyl-phosphate intermediate, a step necessary for subsequent transport of copper across membranes. Neither Cu2+ nor other divalent metals such as Zn2+ or Cd2+ stimulate the formation of phospho-intermediate
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7B has six N-terminal metal-binding domains, MBDs, that sense cytosolic copper levels and regulate ATP7B, mechanism, overview. Mutating MBD2 or MBD3 causes Cys oxidation in other MBDs and loss of copper binding. In contrast, mutation of MBD4 and MBD6 does not alter the redox status and function of other sites. MBD2 and MBD3 work together to regulate access to other metal-binding sites, whereas MBD4 and MBD6 receive copper independently, downstream of MBD2 and MBD3. Structure modeling and molecular dynamics simulations, overview, hydrogen bonding may play a role in the N-ATP7B folding and redox state, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper stimulates both trafficking and phosphorylation of ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
during the catalytic cycle of ATP7A/7B, cytosolic Cu is bound to an intramembrane CPC motif. The -phosphate of ATP is transferred to the invariant aspartate residue of the conserved DKTG motif, with formation of a transient acylphosphate intermediate. Cu is released on the other side of the membrane with concomitant dephosphorylation of aspartate, and the Cu-ATPase returns to its initial state
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B phosphorylation with ATP occurs with diphasic kinetics and is totally copper-dependent
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
the ATP binding cavity contains mainly hydrophobic aliphatic residues, which are involved in van der Waals interactions with the adenine ring of ATP, and a Glu side chain, which forms a crucial hydrogen bond to the amino group of ATP, binding mode of ATP, detailed overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
because the Wilson protein delivers copper to the ferroxidase ceruloplasminm in the liver, it is likely that the Wilson and/or Menkes proteins provide copper to cerulopliasmin made in the retinal pigment epithelium
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
vascular Menkes ATPase plays an essential role in full activity of superoxide dismutase SOD3 through transporting copper to SOD3 in the trans-Golgi network, thereby regulating superoxide anion levels in the vasculature
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
age-dependent expression studies in kidney, role for ATP7A in renal response to changes in copper load
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
immunodetection studies in cells and tissues to analyze specific roles for ATP7A and ATP7B
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
key role of ATP7A in the basolateral export of copper, immunodetection studies
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
role for ATP7B in regulation of renal copper shown
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
role of ATP7A in delivery of copper to milk using transgenic mice that over-express human ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
role of ATP7A in protective effect of copper in neuronal cells
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
in normal conditions ATP7B regulates Cu homeostasis and biosynthesis of holo cuproenzymes and cuproenzyme-related neurotransmission in the brain regions. Neurotoxicity due to abnormal copper accumulation or irregular regulation of cuproenzymes in the critical brain regions by mutation of the ATP7B gene leads to neurological dysfunctions of Wilson disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
role of ATP7A in protective effect of copper in neuronal cells analyzed
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
Ccc2 N-terminal phosphorylation may be coupled to the ATPase domain catalytic cycle
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
enzyme is regulated in response to the change in concentrations of external metals, namely copper and silver, may be involved in copper-homeostasis crucial to the photosynthetic thylakoid function
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
enzyme is regulated in response to the change in concentrations of external metals, namely copper and silver, may be involved in copper-homeostasis crucial to the photosynthetic thylakoid function
-
?
ATP + H2O + Cu2+in
ADP + phosphate + Cu2+out
CopB drives the efflux of Cu2+ from the cell
-
-
?
ATP + H2O + Cu2+in
ADP + phosphate + Cu2+out
the presence of the His residue in the putative transmembrane metal binding site of CopB determines a selectivity for this enzyme that is different for that observed in Cu+/Ag+-ATPases carrying a Cys-Pro-Cys sequence
-
-
?
additional information
?
-
the variation in Cu tolerance of Arabidopsis is regulated by the functional integrity of the Cu-translocating ATPase, HMA5, and in particular the amino acid sequence in several strictly conserved motifs, molecular mechanism of Cu tolerance, overview
-
-
?
additional information
?
-
-
both Menkes and Wilson Disease are severe inherited human diseases involving dysfunctional Cu homeostasis, caused by mutations in the ATP7A and ATP7B genes, respectively. MNK function is linked to activation of the N-methyl-D-aspartic, NMDA, receptor by glycine-glutamate stimulating synaptic release of intracellular Cu, where upon NMDA activation MNK undergoes rapid, reversible relocalization from the TGN to post-Golgi neuronal processes for Cu release. Role for WND in apical Cu excretion and storage in Cu-loaded vesicles, whereas Cu-stimulated MNK trafficking from internal secretory compartments to the basolateral membrane aids Cu re-absorption
-
-
?
additional information
?
-
-
cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases ATP7A and ATP7B
-
-
?
additional information
?
-
-
functional interactions between chemotherapeutic agent cisplatin and ATP7B, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug
-
-
?
additional information
?
-
-
inactivation of Cu-ATPases ATP7A and ATP7B causes Menkes disease and Wilson disease, respectively. In Menkes disease, copper accumulates in kidneys and causes tubular damage, indicating that the renal ATP7B does not compensate for the loss of ATP7A function, copper efflux by ATP7A does not contribute to the lack of trafficking response by ATP7B
-
-
?
additional information
?
-
-
inactivation of the enzyme leads to severe neurodegenerative disorders. ATP7A and ATP7B need a an extensive network of tightly regulated and coordinated protein interactions to facilitate and modulate their activities, the functional deficit of ATP7B causes the Wilson disease
-
-
?
additional information
?
-
-
mutations in ATP7A can lead to Menkes disease which is an X-linked disorder of copper deficiency. Mutations in ATP7B can cause Wilson disease which is an autosomal recessive disorder of copper toxicity. The vast majority of mutations lead to the amino-acid distribution probability increase in mutant ATP7As and decrease in ATP7Bs, quantitative comparison of wild-type and mutant ATP7A and ATP7B, statistical validation, overview
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-
?
additional information
?
-
the catalytic step does not require substantial structural flexibility or rearrangements
-
-
?
additional information
?
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-
the catalytic step does not require substantial structural flexibility or rearrangements
-
-
?
additional information
?
-
study of the mechanism of ATP hydrolysis of a shortened variant of the heavy metal-translocating P-type ATPase CopB. Stoichiometric high-affinity binding of one nucleotide to the protein is demonstrated. The phosphate groups are not involved in nucleotide binding. A model of the hydrolytic mechanism is suggested
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + H2O + Cu2+in
ADP + phosphate + Cu2+out
CopB drives the efflux of Cu2+ from the cell
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper stimulates both trafficking and phosphorylation of ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
Cu-ATPase in the blood-brain barrier controls the penetration of Cu into the brain, lesions to the Cu-ATPase in cerebrovascular endothelial cells are a primary cause of low brain Cu levels in Menkes disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the copper-induced conformational changes could play an important role in the function and regulation of the ATPase in vivo
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B translocates copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes. Disturbed incorporation of copper into the late endosomal lumen from the cytosol by the mutated ATP7B is the main defect of Wilson's disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper-translocating activity of MNK and its copper-induced relocalization to the plasma membrane represent a well coordiated copper homeostasis system. Mutations in MNK which alter either its catalytic activity or/and ability to traffick can be the cause of Menkes disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
relocalization of the enzyme is a physiological process, which may be mediated by copper levels in the breast or by hormones and other events taking place during lactation
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Wilson disease copper-transporting ATPase plays a critical role in the intracellular trafficking of copper. Mutations in this protein lead to the accumulation of a toxic level of copper in the liver, kidney, and brain followed by extensive tissue damage and death
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
autosomal recessive Wilson disease is characterized by copper toxicity believed to result from the loss of ability to export copper from liver to bile and incorporate copper into ceruloplasmin in the liver. Mechanism of alternative splicing serves to regulate the amount of functional Wilson disease protein produced in brain, kidney and placenta
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
responsible for ligating the copper atoms prior to transport across the membrane
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the gene Mc1 is responsible for Menkes disease, an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7A is involved in copper loading observed during iron deficiency. Increased intestinal copper transport is of physiological relevance, as copper plays important roles in overall body iron homeostasis
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
because the Wilson protein delivers copper to the ferroxidase ceruloplasminm in the liver, it is likely that the Wilson and/or Menkes proteins provide copper to ceruloplasmin made in the retinal pigment epithelium
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7A, a copper-transporting P-type ATPase, plays an important role in Cu homeostasis and is affected in Menkes disease
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B is a copper-transporting P-type ATPase present predominantly in liver, hepatic ATPB7 loads cytoplasmic Cu2+ onto newly synthesized ceruloplasmin, the F37-E45 signal sequence is required in vivo, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
ATP7B is a P1-type-ATPase with high selectivity to Cu+
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
kidney-specific regulation of ATP7B, unlike ATP7A, or hepatic ATP7B, which traffics from the TGN to export copper, renal ATP7B does not traffic and therefore is unlikely to mediate copper export. Role for renal ATP7B in intracellular copper storage
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the copper-translocating Menkes, ATP7A or MNK protein, and Wilson, ATP7B or WND protein, P-type ATPases are pivotal for copper homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as MNK in systemic Cu absorption and WND in Cu excretion. MNK and WND Cu-ATPases translocate Cu across biological membranes, MNK participates in vectorial Cu transport across the basolateral membrane and into the bloodstream. Phosphorylation events play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms, overview. MNK is responsible for direct Cu export in response to lactation, where hormonal induction by estrogen, progesterone, insulin and prolactin stimulate the expression and basolateral localization of MNK and the Cu uptake protein Ctr1 to perform a homeostatic function in the mothers tissue
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the enzyme is involved in copper transport, copper homeostasis, and in human cancer progression, overview. When the copper concentration in the hepatocyte increases, ATP7B relocates to the canalicular compartment and excretes excess copper to the bile, intestinal ATPA7 exports the absorbed copper from the enterocytes into the blood stream to supply the copper for the systemic need in a process that involves trafficking of he transporter towards the basolateral membrane. Copper is delivered by specific cytosolic chaperones. ATP7A is essential for the function of a copper-dependent enzyme tyrosinase in the secretory pathway in melanosomes
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
ATP7B has six N-terminal metal-binding domains, MBDs, that sense cytosolic copper levels and regulate ATP7B, mechanism, overview. Mutating MBD2 or MBD3 causes Cys oxidation in other MBDs and loss of copper binding. In contrast, mutation of MBD4 and MBD6 does not alter the redox status and function of other sites. MBD2 and MBD3 work together to regulate access to other metal-binding sites, whereas MBD4 and MBD6 receive copper independently, downstream of MBD2 and MBD3. Structure modeling and molecular dynamics simulations, overview, hydrogen bonding may play a role in the N-ATP7B folding and redox state, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
copper stimulates both trafficking and phosphorylation of ATP7A
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
during the catalytic cycle of ATP7A/7B, cytosolic Cu is bound to an intramembrane CPC motif. The -phosphate of ATP is transferred to the invariant aspartate residue of the conserved DKTG motif, with formation of a transient acylphosphate intermediate. Cu is released on the other side of the membrane with concomitant dephosphorylation of aspartate, and the Cu-ATPase returns to its initial state
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
because the Wilson protein delivers copper to the ferroxidase ceruloplasminm in the liver, it is likely that the Wilson and/or Menkes proteins provide copper to cerulopliasmin made in the retinal pigment epithelium
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
vascular Menkes ATPase plays an essential role in full activity of superoxide dismutase SOD3 through transporting copper to SOD3 in the trans-Golgi network, thereby regulating superoxide anion levels in the vasculature
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
in normal conditions ATP7B regulates Cu homeostasis and biosynthesis of holo cuproenzymes and cuproenzyme-related neurotransmission in the brain regions. Neurotoxicity due to abnormal copper accumulation or irregular regulation of cuproenzymes in the critical brain regions by mutation of the ATP7B gene leads to neurological dysfunctions of Wilson disease
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
the Ccc2 N-terminus encloses two copper-binding domains, M1 and M2, in vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2. Dual role for the Ccc2 N-terminus, namely to receive copper from Atx1 and to convey copper to another domain of Ccc2, overview
-
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
enzyme is regulated in response to the change in concentrations of external metals, namely copper and silver, may be involved in copper-homeostasis crucial to the photosynthetic thylakoid function
-
?
ATP + H2O + Cu2+/in
ADP + phosphate + Cu2+/out
-
enzyme is regulated in response to the change in concentrations of external metals, namely copper and silver, may be involved in copper-homeostasis crucial to the photosynthetic thylakoid function
-
?
additional information
?
-
the variation in Cu tolerance of Arabidopsis is regulated by the functional integrity of the Cu-translocating ATPase, HMA5, and in particular the amino acid sequence in several strictly conserved motifs, molecular mechanism of Cu tolerance, overview
-
-
?
additional information
?
-
-
both Menkes and Wilson Disease are severe inherited human diseases involving dysfunctional Cu homeostasis, caused by mutations in the ATP7A and ATP7B genes, respectively. MNK function is linked to activation of the N-methyl-D-aspartic, NMDA, receptor by glycine-glutamate stimulating synaptic release of intracellular Cu, where upon NMDA activation MNK undergoes rapid, reversible relocalization from the TGN to post-Golgi neuronal processes for Cu release. Role for WND in apical Cu excretion and storage in Cu-loaded vesicles, whereas Cu-stimulated MNK trafficking from internal secretory compartments to the basolateral membrane aids Cu re-absorption
-
-
?
additional information
?
-
-
cisplatin sensitivity of oral squamous carcinoma cells is regulated by Na+,K+-ATPase activity rather than copper-transporting P-type ATPases ATP7A and ATP7B
-
-
?
additional information
?
-
-
functional interactions between chemotherapeutic agent cisplatin and ATP7B, cisplatin binding to ATP7B and/or general changes in cellular copper homeostasis are likely contributors to the increased resistance to the drug
-
-
?
additional information
?
-
-
inactivation of Cu-ATPases ATP7A and ATP7B causes Menkes disease and Wilson disease, respectively. In Menkes disease, copper accumulates in kidneys and causes tubular damage, indicating that the renal ATP7B does not compensate for the loss of ATP7A function, copper efflux by ATP7A does not contribute to the lack of trafficking response by ATP7B
-
-
?
additional information
?
-
-
inactivation of the enzyme leads to severe neurodegenerative disorders. ATP7A and ATP7B need a an extensive network of tightly regulated and coordinated protein interactions to facilitate and modulate their activities, the functional deficit of ATP7B causes the Wilson disease
-
-
?
additional information
?
-
-
mutations in ATP7A can lead to Menkes disease which is an X-linked disorder of copper deficiency. Mutations in ATP7B can cause Wilson disease which is an autosomal recessive disorder of copper toxicity. The vast majority of mutations lead to the amino-acid distribution probability increase in mutant ATP7As and decrease in ATP7Bs, quantitative comparison of wild-type and mutant ATP7A and ATP7B, statistical validation, overview
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
additional information
?
-
-
enzymatic cycle of Ccc2: the ATPase binds Cu(I) at its transport site, a step which induces a conformational change and phosphorylation from ATP. The energy is used to open the transport site on the other side of the membrane and to release Cu(I) into the TGN lumen, the aspartyl-phosphate bound is hydrolyzed
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ag+
Co2+
activity slightly above background as measured in the absence of any such ion
copper
the enzyme contains two Cu(I)-binding sites. Copper binding within the His-Met-loop stabilizes Cu(I) and protects it from oxidation, which may further aid the transfer of copper from ATP7A to acceptor proteins
Cu
Cu+
Cu2+
Mg2+
Ni2+
activity slightly above background as measured in the absence of any such ion
Zn2+
additional information
Ag+
purified CtrA2 protein, stimulation twice as efficient as by Cu2+
Ag+
purified CtrA3 protein, stimulation twice as efficient as by Cu2+
Ag+
the enzyme is activated by silver ions with an apparent affinity in the micromolar range (40% activation at 0.005 mM compared to Cu+)
Ag+
partially activated by Ag+, 55%, of the activation compared to Cu2+
Cu
in HepG2 cells, elevated copper levels stimulates trafficking of ATP7B to pericanalicular vesicles. Mechanism of biliary copper excretion involves ATP7B-mediated vesicular sequestration of copper rather than direct copper translocation across the canalicular membrane
Cu+
the enzyme is preferentially activated by monovalent copper ions with an apparent affinity in the micromolar range (100% activation at 0.005 mM)
Cu+
partially activated by Cu+, 22% of the activation compared to Cu2+
Cu+
-
formation of the vanadate-sensitive phosphoenzyme by purified Menkes diesease protein is activated by Cu+. Cu+ interacts with Menkes disease protein in a cooperative manner and with high affinity in the sub-micromolar range
Cu+
structural characterization of the apo- and copper(I)-form of the third domain of ATP7A. Investigation of the interaction of MNK3 (the third metal-binding domain, a copper(I)-transporrting ATPase) with the partner human protein HAH1. MNK3 is the most differentiated metal-binding domain in ATP7A. Metallation of MNK3 could be an event quite suited to signal high intracellular copper(I) concentration and could trigger the appropriate response
Cu+
-
Cu+ stimulates catalytic activity of ATP7B, inducing the hydrolysis of ATP via formation of an acyl-phosphate intermediate, a step necessary for subsequent transport of copper across membranes. Neither Cu2+ nor other divalent metals such as Zn2+ or Cd2+ stimulate the formation of phospho-intermediate
Cu+
the metal-dependent conformational changes observed in the N-terminal region of the ATPase may not require the presence of the CXXC motif on every domain, as long as the domain has the proper shape, which is an heavy metal-associated-domain-like fold, and as long as some of them contain the CXXC metal binding site. At a certain point during the cooperative binding of Cu(I), protein/protein interactions among the heavy metal-associated -domains begin to dominate the conformational changes in rat ATP7B, while metal binding to the heavy metal-associated -domains makes a smaller contribution
Cu2+
purified CtrA2 protein, stimulated by Cu2+ in the presence of DTT, not stimulated by Cu2+
Cu2+
purified CtrA3 protein, stimulated by Cu2+, no stimulation by Cu2+ in the presence of DTT
Cu2+
activated by Cu2+ with high apparent affinity (K1/2 = 0.00028 mM)
Cu2+
-
activates inducing phosphorylation of the enzyme, inhibition is observed above 0.005 mM
Cu2+
-
six binding sites, may be reduced to Cu+ upon binding, copper binding is cooperative and induces conformational changes in the enzyme
Cu2+
-
six binding sites, regulates enzyme modulating catalytic activity, posttranslational modification and intracellular localization
Cu2+
CopB-B has heavy metal stimulated phosphatase activity, which is half maximal in the presence of 80 microM Cu2+
Mg2+
activity slightly above background as measured in the absence of any such ion
Mg2+
-
required for the hydrolysis of ATP, suggesting that MgATP2+ is the substrate
Mg2+
not necessary for nucleotide association but essential for the phosphatase activity
Zn2+
activity slightly above background as measured in the absence of any such ion
Zn2+
-
zinc binds with a stoichiometry of 6 to 1 and induces a conformational change in the N-terminal domain that is different from those observed for copper binding, leading to a loss of secondary structure in the domain
additional information
CopB and its homologs are distinguished by a metal binding sequence Cys-Pro-His in their sixth transmembrane segment and a His-rich N-terminal metal binding domain
additional information
-
CopB and its homologs are distinguished by a metal binding sequence Cys-Pro-His in their sixth transmembrane segment and a His-rich N-terminal metal binding domain
additional information
solution structure of the reduced and Cu(I) bound forms of the first metal binding sequence of ATP7A. The XMTCXXC sequence may play a prominent role in the dynamics of the metal bidning loop. the residues of the metal binding loop may transduce slight changes in the tertiary fold of the protein that account for metal specificity in Cu(I) bound MNK1
additional information
-
solution structure of the reduced and Cu(I) bound forms of the first metal binding sequence of ATP7A. The XMTCXXC sequence may play a prominent role in the dynamics of the metal bidning loop. the residues of the metal binding loop may transduce slight changes in the tertiary fold of the protein that account for metal specificity in Cu(I) bound MNK1
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
thiol
activity of CtrA3 decreased at concentrations of 20 mM and above
additional information
-
in hepatocytes, ATP7B-mediated efflux does not play a major role in determining cell sensitivity to cis-diamminedichloroplatinum
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Atx1
-
the metallo-chaperone Atx1 interacts with the N-terminus of Ccc2 essentially required for the copper delivery to the trans-Golgi network. Atx1 does not activate the Ccc2-derived ATPase lacking its N-terminus
-
cis-diamminedichloroplatinum
-
DDP, stimulates catalytic phosphorylation of ATP7B
-
dithioerythritol
-
GSH, dithiothreitol or dithioerythritol are required for activity
dithiothreitol
-
GSH, dithiothreitol or dithioerythritol are required for activity
glutaredoxin
is essential for ATPase function and catalysis either the reduction of intramolecular disulphide bonds or the deglutathionylation of the cysteine residues within the CxxC motifs to facilitate copper-binding for subsequent transport
glutaredoxin-1
-
is essential in interaction with ATP7A and ATP7B via their N-termini for stabilizing their activities
-
cysteine
stimulated by, optimum concentration of 15 mM for CtrA3
additional information
activity depends on addition of extraneous lipid, similar effects for polar lipids of Escherichia coli, phosphatidylcholine of Glycine max, total extract of Aquifex aeolicus lipids and for the synthetic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
-
additional information
activity depends on addition of extraneous lipid, similar effects for polar lipids of Escherichia coli, phosphatidylcholine of Glycine max, total extract of Aquifex aeolicus lipids and for the synthetic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
Km-value for copper varies insignificantly between different mutants and wild-type enzyme
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.081
-
partially purifed recombinant ATP7B in microsomes, copper-dependent, steady-state ATPase, 37°C, pH 6.0, in presence of copper and copper chelator
0.112
-
partially purifed recombinant ATP7B in microsomes, copper-dependent, steady-state ATPase, 37°C, pH 6.0 in presence of copper
additional information
additional information
CtrA2 protein shown to have a CPC metal-binding sequence in TM6 and a CxxC metal-binding N-terminal domain, substrate ion-induced activity on lipids, pH, temperature, ionic strength and thiols tested, CtrA2 protein activated by Ag+ and Cu2+, transport of reduced copper ion
additional information
CtrA2 protein shown to have a CPC metal-binding sequence in TM6 and a CxxC metal-binding N-terminal domain, substrate ion-induced activity on lipids, pH, temperature, ionic strength and thiols tested, CtrA2 protein activated by Ag+ and Cu2+, transport of reduced copper ion
additional information
CtrA3 protein has a CPH metal-binding motif in TM6 and a histidine-rich N-terminal metal-binding domain substrate ion-induced activity on lipids, pH, temperature, ionic strength and thiols, eight membrane-spanning alpha-helices per monomer determined by structural analysis, arrangement of the six central helices surrounding the ion-binding site in the membrane conserved, sequence alignment and fitting of domains to the projection map
additional information
CtrA3 protein has a CPH metal-binding motif in TM6 and a histidine-rich N-terminal metal-binding domain substrate ion-induced activity on lipids, pH, temperature, ionic strength and thiols, eight membrane-spanning alpha-helices per monomer determined by structural analysis, arrangement of the six central helices surrounding the ion-binding site in the membrane conserved, sequence alignment and fitting of domains to the projection map
additional information
enhancer element with sufficient regulatory information to rescue DmATP7 mutant flies to adulthood, regulation of DmATP7 expression shown to be not used to limit copper absorption in toxic copper conditions, functional role for copper transport in neuronal tissues indicated, role for export of copper from midgut cells supported by localization studies
additional information
-
enhancer element with sufficient regulatory information to rescue DmATP7 mutant flies to adulthood, regulation of DmATP7 expression shown to be not used to limit copper absorption in toxic copper conditions, functional role for copper transport in neuronal tissues indicated, role for export of copper from midgut cells supported by localization studies
additional information
immunoblot analysis and immunofluorescence labelling, electron microscopy immunogold labelling applied for subcompartmental localization
additional information
-
immunoblot analysis and immunofluorescence labelling, electron microscopy immunogold labelling applied for subcompartmental localization
additional information
11 missense variants of ATP7B identified in Wilson disease patients analyzed by capacity of functional complementation of a yeast mutant strain disrupted by the ATP7B gene ortholog CCC2, solution structures and homology of ATP7B domains used to predict effects of each variant
additional information
-
11 missense variants of ATP7B identified in Wilson disease patients analyzed by capacity of functional complementation of a yeast mutant strain disrupted by the ATP7B gene ortholog CCC2, solution structures and homology of ATP7B domains used to predict effects of each variant
additional information
analysis of ATP7B at the cell surface by expression studies in intact cells, presence of ATP7B at the plasma membrane shown by electron microscopy, freeze-fracture experiments and surface luminescence measurements, delivery to the plasma membrane of oocytes unaffected by deletion of the N-terminal copper-binding domain or the inactivating mutation of catalytic Asp1027, surface targeting decreased for ATP7B variants with mutations in the ATP-binding site or in the copper-binding site, ligand-stabilized conformations important for ATP7B trafficking
additional information
ATP-dependent accumulation of cisplatin indicated, cisplatin shown to induce acyl-phosphorylation of ATP7B but at slower rate than copper, Vmax value for cisplatin shown to be nearly 28fold lower than that for copper
additional information
biochemical and structural characteristics of human copper-ATPase, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal binding pockets of N-terminal domain and ATP-binding domain
additional information
biochemical and structural characteristics of human copper-ATPase, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal binding pockets of N-terminal domain and ATP-binding domain
additional information
-
biochemical and structural characteristics of human copper-ATPase, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal binding pockets of N-terminal domain and ATP-binding domain
additional information
biochemical and structural characteristics of human copper-ATPases, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, dual role of copper-transporting ATPase ATP7B in hepatocyte, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal-binding pockets of N-terminal domain and ATP-binding domain
additional information
biochemical and structural characteristics of human copper-ATPases, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, dual role of copper-transporting ATPase ATP7B in hepatocyte, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal-binding pockets of N-terminal domain and ATP-binding domain
additional information
-
biochemical and structural characteristics of human copper-ATPases, unique sequence motifs in regulating ATP7A and ATP7B activity and trafficking, dual role of copper-transporting ATPase ATP7B in hepatocyte, transmembrane organization and catalytic cycle, sequence and predicted folding of transmembrane portion, metal-binding pockets of N-terminal domain and ATP-binding domain
additional information
discussion on identification of copper transporters ATP7A and ATP7B as platinum drug transporters, structural, functional and mechanistic aspects summarized, future research directions improving efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporter activities summarized
additional information
discussion on identification of copper transporters ATP7A and ATP7B as platinum drug transporters, structural, functional and mechanistic aspects summarized, future research directions improving efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporter activities summarized
additional information
-
discussion on identification of copper transporters ATP7A and ATP7B as platinum drug transporters, structural, functional and mechanistic aspects summarized, future research directions improving efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporter activities summarized
additional information
effect of hormone treatment on expression analyzed by Western blot, indirect immunocytochemistry and real-time PCR, copper transport and accumulation, insulin and oestrogen increase ATP7A mRNA and protein levels and alter the localization of ATP7A towards the basolateral membrane in a copper-independent manner, insulin and oestrogen increase the transport of copper across basolateral membrane, model of insulin and oestrogen effect on ATP7A and ATP7B in the placenta
additional information
effect of hormone treatment on expression analyzed by Western blot, indirect immunocytochemistry and real-time PCR, copper transport and accumulation, insulin and oestrogen increase ATP7A mRNA and protein levels and alter the localization of ATP7A towards the basolateral membrane in a copper-independent manner, insulin and oestrogen increase the transport of copper across basolateral membrane, model of insulin and oestrogen effect on ATP7A and ATP7B in the placenta
additional information
effect of hormone treatment on expression analyzed by Western blot, indirect immunocytochemistry and real-time PCR, copper transport and accumulation, levels of ATP7B decreased in response to insulin, protein shown to localize in a tight perinuclear region, corresponding decrease in copper efflux across the apical membrane, model of insulin and oestrogen effect on ATP7A and ATP7B in the human placenta
additional information
effect of hormone treatment on expression analyzed by Western blot, indirect immunocytochemistry and real-time PCR, copper transport and accumulation, levels of ATP7B decreased in response to insulin, protein shown to localize in a tight perinuclear region, corresponding decrease in copper efflux across the apical membrane, model of insulin and oestrogen effect on ATP7A and ATP7B in the human placenta
additional information
histoculture drug response assay for prediction of drug sensitivity of clinical cancers applied, ATP7A expression shown to enhance efflux rates of doxorubicin and 7-ethyl-10-hydroxy-camptothecin (SN-38) from cells, increased uptake of 7-ethyl-10-hydroxy-camptothecin in membrane vesicles indicated, ATP7A-expressing colon cancer cells shown to be more resistant to 7-ethyl-10-hydroxy-camptothecin than ATP7A-negative cells
additional information
-
histoculture drug response assay for prediction of drug sensitivity of clinical cancers applied, ATP7A expression shown to enhance efflux rates of doxorubicin and 7-ethyl-10-hydroxy-camptothecin (SN-38) from cells, increased uptake of 7-ethyl-10-hydroxy-camptothecin in membrane vesicles indicated, ATP7A-expressing colon cancer cells shown to be more resistant to 7-ethyl-10-hydroxy-camptothecin than ATP7A-negative cells
additional information
immunocytochemistry experiments, co-localization studies performed, consequences of ATP7B inactivation in knock-out mice analyzed, studies on Wilson disease causing mutation H1069Q summarized
additional information
microscopy and cell fractionation studies applied to study cellular distribution of ATP7B, profile of radio-labelled copper excretion into the bile measured, evidence of copper excretion by transcytosis across the hepatocyte and by paracellular transport throughout the tight junctions discussed
additional information
molecular mechanisms of ATP7A and ATP7B function and the effects of disease-causing mutations, genotype-phenotype correlations in the development of Menke disease and Wilson disease
additional information
structural features and major functional domains of human copper-ATPases shown, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
structural features and major functional domains of human copper-ATPases shown, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
-
structural features and major functional domains of human copper-ATPases shown, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
structural features and major functional domains of human copper-ATPases, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
structural features and major functional domains of human copper-ATPases, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
-
structural features and major functional domains of human copper-ATPases, transport mechanism and regulation of catalytic activity, localization and trafficking in polarized cells, role metal-binding subdomains, comparison with orthologs from other species
additional information
ATP7A xpressed to a variable degree throughout the kidney, age-dependent intracellular localization, copper elevation results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, ATP7A plays a major role in exporting copper via basolateral membranes and protects renal tissue against copper overload
additional information
ATP7A xpressed to a variable degree throughout the kidney, age-dependent intracellular localization, copper elevation results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, ATP7A plays a major role in exporting copper via basolateral membranes and protects renal tissue against copper overload
additional information
connection between copper homeostasis and NMDA receptor activity, ATP7A required for copper-dependent effects
additional information
copper concentration in the mammary gland reduced in transgenic mice, immunofluorescence analysis of mammary gland tissue, tissue copper concentration, mRNA levels of endogenous ATP7A and ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice, ATP7A plays a role in removing excess copper from mammary epithelial cells rather than supplying copper to milk
additional information
copper concentration in the mammary gland reduced in transgenic mice, immunofluorescence analysis of mammary gland tissue, tissue copper concentration, mRNA levels of endogenous ATP7A and ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice, ATP7A plays a role in removing excess copper from mammary epithelial cells rather than supplying copper to milk
additional information
-
copper concentration in the mammary gland reduced in transgenic mice, immunofluorescence analysis of mammary gland tissue, tissue copper concentration, mRNA levels of endogenous ATP7A and ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice, ATP7A plays a role in removing excess copper from mammary epithelial cells rather than supplying copper to milk
additional information
immunodetection studies to analyze specific roles for ATP7A and ATP7B, partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates
additional information
immunodetection studies to analyze specific roles for ATP7A and ATP7B, partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates
additional information
-
immunodetection studies to analyze specific roles for ATP7A and ATP7B, partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates
additional information
mRNA levels of endogenous ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice
additional information
mRNA levels of endogenous ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice
additional information
-
mRNA levels of endogenous ATP7B and of ATP7B protein unaltered in mammary gland of transgenic mice
additional information
partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates, specific role of ATP7B in tissues, in which it is co-expressed with ATP7A, may involve delivery of copper to ceruloplasmin, apical copper export and/or fine tuning of intracellular copper by sequestration of copper in the vesicles
additional information
partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates, specific role of ATP7B in tissues, in which it is co-expressed with ATP7A, may involve delivery of copper to ceruloplasmin, apical copper export and/or fine tuning of intracellular copper by sequestration of copper in the vesicles
additional information
-
partial overlap in the intracellular localization of ATP7A and ATP7B due to different sorting and trafficking fates, specific role of ATP7B in tissues, in which it is co-expressed with ATP7A, may involve delivery of copper to ceruloplasmin, apical copper export and/or fine tuning of intracellular copper by sequestration of copper in the vesicles
additional information
renal copper homeostasis requires functional ATP7B, coexpression with ATP7A, kidneys of ATP7b(-/-) mice reveals metabolic alterations manifested by the appearance of highly fluorescent deposits, lack of notable copper accumulation in the Atp7b(-/-) kidney due to compensatory export of copper by ATP7A
additional information
renal copper homeostasis requires functional ATP7B, coexpression with ATP7A, kidneys of ATP7b(-/-) mice reveals metabolic alterations manifested by the appearance of highly fluorescent deposits, lack of notable copper accumulation in the Atp7b(-/-) kidney due to compensatory export of copper by ATP7A
additional information
connection between copper homeostasis and NMDA receptor activity, ATP7A required for copper-dependent effects
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.6 - 6.9
ability of wild-type ATP7B to transport copper when exposed to 2 microM copper shown to be greater at pH 4.6 than at pH 6.9, ATP-dependent accumulation of cisplatin shown at 4.6
5 - 9
5 - 9
ATPase activities stimulated by Cu2+ measured at different pH values
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
20 - 90
20 - 90
maximum at 75°C, decreased to between 50% and 70% of this value at 90°C, significantly active down to 50°C
20 - 90
maximum at 75°C, shown to be decreased to between 50% and 70% of this value at 90°C, shown to be completely inactive at 50°C or below
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
246908, 246909, 246910, 246914, 246917, 246918, 246919, 246920, 654428, 655950, 655951, 655952, 656013, 656023, 656041, 656237
-
-
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ATP7B; 2 weeks old and 20 weeks old, wild-type and deficient in copper-transporting ATPase ATP7B (-/-)
SwissProt
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
cellular distribution of ATP7B, stable ATP7B pool localized to the tight junctions that seal the bile canaliculi shown
brenda
ATP7B is expressed in bile duct epithelial cells, where it may mediate copper secretion into bile fluid
brenda
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expression is greater in lactating tissue than in nonlactating tissue, detected in luminal epithelial cells of the alveoli and ducts but not in myoepithelial cells
brenda
ATP7A shown to be expressed in 23.5% of clinical colon cancer specimens but not in the adjacent normal epithelium
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ATP7A is present on apical domains of duodenal enterocytes in control rats and on brush-border and basolateral membrane domains in iron-deprived rats
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airway, cell type-specific expression of ATP7A and ATP7B in airway epithelial cells
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the overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplantin-based chemotherapy
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ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum
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presence of ATP7A in the axons of postnatal, but not adult, optic nerve
brenda
Menkes protein could be involved in copper secretion from acinar cells into saliva
brenda
additional information
ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons
brenda
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intensely detected in neuronal cells of the hippocampal formation, olfactory bulbs, cerebellum, cerebral cortex and nuclei in the brainstem
brenda
ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum
brenda
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fibroblasts from the female Menkes translocation patient show no detectable expression of the transcript, five additional fibroblast lines from unrelated Menkes patients show alterations in the expression of this gene
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isolated from Menkes disease patients, transfection with ATP7A
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trafficking of ATP7B in Hep-G2 cells is not regulated by cis-diamminedichloroplatinum, DDP, while Huh7 cells show a biphasic response with a sharp 50% decrease in cell survival
brenda
ATP7B interaction with p62 is a key component of the copper-induced trafficking pathway that delivers ATP7B to subapical vesicles of hepatocytes for the removal of excess copper into bile
brenda
ATP7B is observed close to the plasma membrane, both at the sinusoidal and at the biliary pole
brenda
-
ATP7A and ATP7B are co-expressed in proximal and distal epithelial cells
brenda
ATP7A protein 10fold to 20fold higher in transgenic than in control mice
brenda
main neurons of leg, wing margin, labellum, maxillary palps and third antennal segment
brenda
-
hippocampal, neuronal MNK trafficking may occur independently of its catalytic cycle
brenda
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polarized sorting of the Cu2+ transporter ATP7B to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the sigma1 subunit of the clathrin adaptor AP-1. Under basal Cu2+ conditions, ATP7B is localized to the trans-Golgi network and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative sigma1 mutant results in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Addition of high Cu2+ concentrations causes loss of trans-Golgi network localization and somatodendritic polarity of ATP7B
brenda
Menkes disease protein, i.e. ATP7A is present in the syncytiotrophoblast, cytotrophoblast and the fetal vascular endothelial cells. Placental level does not change across pregancy
brenda
Wilson disease protein is present only in the syncytiotrophoblast
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both Cu-ATPases ATP7A and ATP7B are expressed within retinal pigment epithelium
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Menkes disease protein, i.e. ATP7A is present in the syncytiotrophoblast, cytotrophoblast and the fetal vascular endothelial cells
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Wilson disease protein is present only in the syncytiotrophoblast
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fetal. Menkes disease protein, i.e. ATP7A
brenda
additional information
no ATP7B expression in normal hepatic cells
brenda
additional information
-
expression levels of ATP7A and other Cu homeostasis proteins are not significantly affected by Cu exposure
brenda
additional information
-
when the copper concentration in the hepatocyte increases, ATP7B relocates to the canalicular compartment and excretes excess copper to the bile, intestinal ATPA7 exports the absorbed copper from the enterocytes into the blood stream to supply the copper for the systemic need in a process that involves trafficking of he transporter towards the basolateral membrane
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
inner membrane of the chloroplast envelope
brenda
within ARPE-19 cell the Wilson disease protein shows a perinuclear and cytoplasmic distribution
brenda
COMM-domain-containing 1 maintains the amount of Atp7b and facilitates recruitment of the enzyme from cytoplasmic vesicles to the trans-Golgi network membrane
brenda
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mainly localized in the late endosomes in both the steady and copper-loaded states. ATP7B translocates copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes
brenda
ATP7B interaction with p62 is a key component of the copper-induced trafficking pathway that delivers ATP7B to subapical vesicles of hepatocytes for the removal of excess copper into bile
brenda
in HepG2 cells, elevated copper levels stimulates trafficking of ATP7B to pericanalicular vesicles. Mutations of an endocytic retrieval signal in ATP7B cause the protein to constitutively localize to vesicles and not to plasma membrane. The vesicular compartment is the final trafficking destination for ATP7B
brenda
within ARPE-19 cell the Wilson disease protein shows a perinuclear and cytoplasmic distribution
-
brenda
heterogeneous distribution, small clusters
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the enzyme redistributes from Golgi apparatus into vesicles in high copper conditions
brenda
additional information
PAA1 functions in copper transport over the envelope membrame, required for copper delivery to plastocyanin
brenda
PAA2 functions in copper transport over the thylakoid membrame, required for copper delivery to plastocyanin
brenda
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the enzyme is predominantly localized to the Golgi apparatus of cells, the enzyme continuously recycles between the Golgi and the plasma membrane, and elevated copper shifts the steady-state distribution from the Golgi to the plasma membrane
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the enzyme exhibits a tight Golgi pattern in low copper
brenda
COMM-domain-containing 1 maintains the amount of Atp7b and facilitates recruitment of the enzyme from cytoplasmic vesicles to the trans-Golgi network membrane
brenda
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perinuclear location of ATP7A. IFN-gamma activation of macrophages is associated with partial redistribution of ATP7A to the phagolysosomal compartment, IFN-gamma triggers the trafficking of ATP7A
brenda
copper excess shown to provoke massive download of ATP7B retained in the Golgi network into the bile canalicular membrane
-
brenda
important role of Golgi network for ATP7A-related multidrug resistance
-
brenda
trafficking from the trans-Golgi network to endocytic vesicles in response to various signals
-
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-
Menkes ATPase colocalizes with superoxide dismutase SOD3 in the trans-Golgi network of the secretory pathway
-
brenda
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the enzyme continuously recycles between the Golgi and the plasma membrane, and elevated copper shifts the steady-state distribution from the Golgi to the plasma membrane
brenda
at or proximal to basolateral plasma membrane of midgut cells
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basolateral membrane of both the midgut and the Malpighian tubules. The enzyme translocates towards the basolateral membrane when exposed to elevated copper
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ATP7A protein levels are increased in brush-border and basolateral membrane vesicles isolated from iron-defiocient rats
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targeting to plasma membrane shown, wild-type and recombinant protein
brenda
ATP7B is a 165-kDa protein with eight transmembrane segments and most of the soluble parts exposed to the cytosol
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2 week old mice, vicinity of the basolateral membrane
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basolateral membrane of mammary epithelial cells in lactating mice
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20 week old mice, predominantly in intracellular vesicles
-
brenda
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polarized sorting of the Cu2+ transporter ATP7B to the somatodendritic domain of rat hippocampal neurons is mediated by recognition of dileucine-based signals in the cytosolic domains of the proteins by the sigma1 subunit of the clathrin adaptor AP-1. Under basal Cu2+ conditions, ATP7B is localized to the trans-Golgi network and the plasma membrane of the soma and dendrites but not the axon. Mutation of a dileucine-based signal in ATP7B or overexpression of a dominant-negative sigma1 mutant results in nonpolarized distribution of ATP7B between the somatodendritic and axonal domains. Addition of high Cu2+ concentrations causes loss of trans-Golgi network localization and somatodendritic polarity of ATP7B
brenda
additional information
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in nonlactating breast epithelial cells the enzyme has a predominantly perinuclear distribution, in lactating breast tissue the enzyme appears as a granular, diffuse pattern that extends beyond the perinuclear region of the cell in both alveoli. Relocalization of the enzyme is a physiological process, which may be mediated by copper levels in the breast or by hormones and other events taking place during lactation
-
brenda
additional information
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intracellular localization of ATP7A in various tissues is not affected by Cu exposure
-
brenda
additional information
-
mechanisms for copper-ATPase trafficking, detailed overview
-
brenda
additional information
-
immunohistochemic localization analysis, overview
-
brenda
additional information
-
IFN-gamma and lipopolysaccharides stimulate copper-dependent ATP7A trafficking to post-Golgi vesicles that overlap with the phagosome, overview
-
brenda
additional information
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immunohistochemic localization analysis, overview
-
brenda
additional information
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mechanisms for copper-ATPase trafficking, detailed overview
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
malfunction
-
deletion mutant analysis demonstrates that CopA is an effective copper pump at low and high copper concentrations. The DELTAcopA mutant shows highly reduced growth at 2 mM. High toxicity of copper to the DELTAcopA
malfunction
-
deletion mutant analysis demonstrates that CopB is low-affinity copper export ATPase. For the DELTAcopB mutant strain 1.4 mM CuSO4 is needed to slow the onset and beginning of stationary phase at lower levels
malfunction
inactivation of ATP7A results in the neurodegenerative disorder Menkes disease
malfunction
mutations in the gene encoding ATP7B cause copper toxicity (Wilson disease) by altering enzyme trafficking and stability
malfunction
-
ran1 mutants display ethylene-like responses to the ethylene antagonist trans-cyclooctene and have altered copper homeostasis
malfunction
Wilson disease is caused by mutations in the Cu-transporting ATPase ATP7B
metabolism
-
copper delivery to the secretory pathway in yeast, and enzymatic cycle of Ccc2, modelling, overview
metabolism
-
the catalytic cycle of ATP7A/7B is coupled to their intracellular trafficking, and these activities endow them with the biosynthetic and homeostatic functions that underlie the diverse range of physiological processes that depend upon their activities
metabolism
-
copper delivery to the secretory pathway in yeast, and enzymatic cycle of Ccc2, modelling, overview
-
metabolism
-
copper delivery to the secretory pathway in yeast, and enzymatic cycle of Ccc2, modelling, overview
-
physiological function
ATP7A and ATP7B are two human P1B-type ATPases that have a crucial role in maintaining copper(I) homeostasis
physiological function
-
ATP7A and ATP7B are two key proteins that regulate the Cu status of the body. They transport Cu across cellular membranes for biosynthetic and protective functions, enabling Cu to fulfill its role as a catalytic and structural cofactor for many essential enzymes, and to prevent a toxic build-up of Cu inside cells. A variety of regulatory mechanisms operate at transcriptional and post-translational levels to ensure adequate Cu supplies for both physiological and pathophysiological processes. ATP7B transports Cu across the apical surface implicating it as the major means of Cu secretion into milk during lactation. Both Cu-ATPases are expressed in the intestine and kidney and appear to have distinct but complementary functional roles. ATP7A is essential for dietary Cu absorption and mediates Cu transfer across the basolateral membrane of intestinal enterocytes into the portal circulation. ATP7B mayfine-tune intestinal Cu absorption, either via Cu excretion from the apical surface of enterocytes, and/or through vesicular sequestration of excess Cu in enterocytes that are regularly lost by shedding. In the kidney, ATP7A mediates Cu transport across the basolateral membrane for reabsorption into the blood and protection against Cu overload. Hence, ATP7A has a house-keeping role maintaining renal Cu homeostasis. ATP7B, which did not redistribute in response to Cu, more likely has a role in fine-tuning intracellular Cu balance through Cu storage in intracellular compartments
physiological function
-
ATP7A and ATP7B are two key proteins that regulate the Cu status of the body. They transport Cu across cellular membranes for biosynthetic and protective functions, enabling Cu to fulfill its role as a catalytic and structural cofactor for many essential enzymes, and to prevent a toxic build-up of Cu inside cells. A variety of regulatory mechanisms operate at transcriptional and post-translational levels to ensure adequate Cu supplies for both physiological and pathophysiological processes. In the cerebellum, Atp7a may have a homeostatic role maintaining intracellular Cu levels, while Atp7b has a biosynthetic role delivering Cu to enzymes such as ceruloplasmin. In retinal pigment epithelium ATP7A and ATP7B may control Cu transport to the outer retina, as well as Cu delivery to tyrosinase for melanogenesis within the retinal pigment epithelium, and to ceruloplasmin and hephaestin to maintain iron homeostasis
physiological function
-
ATP7A-dependent copper transport is required for bactericidal activity of RAW-264.7 macrophages
physiological function
-
ATP7B is a P-type ATPase required for copper homeostasis and related to Wilson disease of humans
physiological function
ATP7B is essential for human copper homeostasis and normal liver function
physiological function
-
Botrytis cinerea requires copper-containing proteins for infection of hosts, i.e. a large number of plant species, including many commercially important vegetables, fruits, and ornamentals. In the absence of the copper-transporting ATPase BcCCC2, these proteins are inactive
physiological function
-
copper delivery to the trans-Golgi network involves interactions between the metallo-chaperone Atx1 and the N-terminus of Ccc2, the P-type ATPase responsible for copper transport across trans-Golgi network membranes. Disruption of the Atx1-Ccc2 route leads to cell growth arrest in a copper-and-iron-limited medium, Atx1-Ccc2 and intra-Ccc2 domain-domain interactions, overview
physiological function
-
expression of the copper transporter ATP7B in ciliated airway cells is required for detoxification of the methylated caffeine silver acetate compound, SCC1, in the airway epithelium. The cytotoxicity of SCC1-treated airway epithelial cell cultures derived from either wild type or ATP7B null mice littermates is compared, loss of total cells and ciliated cells is significantly greater in ATP7B-/- than in wild type airway epithelial cell
physiological function
-
Menkes copper-translocating P-type ATPase, ATP7A, is a critical copper transport protein functioning in systemic copper absorption and supply of copper to cuproenzymes in the secretory pathway. Mutations in ATP7A can lead to the usually lethal Menkes disease. ATP7A function is regulated by copper-responsive trafficking between the trans-Golgi Network and the plasma membrane
physiological function
-
the bacterial copper-trafficking proteins CopZ, an Atx1-like chaperone, and CopA, a Menkes-like P-type ATPase transporter, are important for Cu(I)-detoxification in Bacillus subtilis, they have the capacity to bind multiple Cu(I) ions
physiological function
-
the enzyme is involved in the cbb3 assembly and in cbb3 oxidase biogenesis
physiological function
-
the enzyme is involved in the cbb3 assembly and in cbb3 oxidase biogenesis
physiological function
-
the enzyme is involved only in the cbb3 assembly. CtpA is likely a copper transporter that supplies copper-requiring proteins in the membrane with this metal. Although CtpA shares significant sequence homologies with the homeostasis copper efflux P1B-type ATPases including the bacterial CopA and the human ATP7A and ATP7B, disruption of ctpA did not result in any sensitivity to excess copper. Thus, CtpA is not crucial for copper tolerance but is involved in the assembly of membrane and periplasmic copper enzymes in this bacterium
physiological function
transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body
physiological function
-
CopA is an effective copper pump at low and high copper concentrations. CopA and CopB act as resistance factors to copper ions at overlapping concentrations. CopA is also involved in resistance to silver
physiological function
CopB drives the efflux of Cu2+ from the cell
physiological function
-
CopB is low-affinity copper export ATPase. CopA and CopB act as resistance factors to copper ions at overlapping concentrations. CopB is also involved in resistance to silver
physiological function
-
copper transporter RAN1 is essential for biogenesis of ethylene receptors in Arabidopsis. The enzyme also delivers silver ions to the ethylene receptors
physiological function
PAA1 is a high affinity Cu(I) transporter of the chloroplast envelope. The sensitivity to copper and silver correlates with the presence of a functional enzyme
physiological function
the enzyme is able to transport copper to the cupro-enzyme tyrosinase, and under elevated copper conditions, it is able to traffic towards the plasma membrane and efflux copper
physiological function
the enzyme pumps copper from the cytosol to the Golgi lumen
physiological function
-
a loss-of-function mutant line shows no apparent defect in in vivo blood stage growth. Parasite transmission through the mosquito vector is severely affected, but not entirely abolished. Male and female gametocytes are abundant in mutant parasites, but activation of male microgametes and exflagellation are strongly impaired. This defect can be mimicked by addition of the copper chelator neocuproine to wild-type gametocytes. Female fertility is also severely abrogated
physiological function
either of P1B-type ATPases, CopA or GolT, is needed to activate periplasmic Cu,Zn-superoxide dismutase. A CopA/GolT double mutant accumulates inactive Cu,Zn-superoxide dismutase which can be activated by copper-supplementation in vitro. In contrast, either single ATPase mutant accumulates fully active Cu,Zn-superoxide dismutase
physiological function
in a CopA deficient mutant under aerobiosis, the chlorophyll biosynthesis pathway is affected by excess copper resulting in a substantial decrease of the photosystem. Under low copper concentrations, the mutant accumulates protochlorophyllide. Increase of copper concentration leads to a complete lack of chlorophyll synthesis
physiological function
plastid copper levels control PAA2 stability. Plastocyanin, which is the target of PAA2 mediated copper delivery in thylakoids, is a major determinant of this regulatory mechanism
physiological function
-
a loss-of-function mutant line shows no apparent defect in in vivo blood stage growth. Parasite transmission through the mosquito vector is severely affected, but not entirely abolished. Male and female gametocytes are abundant in mutant parasites, but activation of male microgametes and exflagellation are strongly impaired. This defect can be mimicked by addition of the copper chelator neocuproine to wild-type gametocytes. Female fertility is also severely abrogated
-
physiological function
-
copper delivery to the trans-Golgi network involves interactions between the metallo-chaperone Atx1 and the N-terminus of Ccc2, the P-type ATPase responsible for copper transport across trans-Golgi network membranes. Disruption of the Atx1-Ccc2 route leads to cell growth arrest in a copper-and-iron-limited medium, Atx1-Ccc2 and intra-Ccc2 domain-domain interactions, overview
-
physiological function
-
in a CopA deficient mutant under aerobiosis, the chlorophyll biosynthesis pathway is affected by excess copper resulting in a substantial decrease of the photosystem. Under low copper concentrations, the mutant accumulates protochlorophyllide. Increase of copper concentration leads to a complete lack of chlorophyll synthesis
-
physiological function
-
either of P1B-type ATPases, CopA or GolT, is needed to activate periplasmic Cu,Zn-superoxide dismutase. A CopA/GolT double mutant accumulates inactive Cu,Zn-superoxide dismutase which can be activated by copper-supplementation in vitro. In contrast, either single ATPase mutant accumulates fully active Cu,Zn-superoxide dismutase
-
physiological function
-
copper delivery to the trans-Golgi network involves interactions between the metallo-chaperone Atx1 and the N-terminus of Ccc2, the P-type ATPase responsible for copper transport across trans-Golgi network membranes. Disruption of the Atx1-Ccc2 route leads to cell growth arrest in a copper-and-iron-limited medium, Atx1-Ccc2 and intra-Ccc2 domain-domain interactions, overview
-
additional information
-
ATP7B overexpression transfers a stable, positive selection advantage to MSCs in a high copper environment
additional information
-
CopZ and CopA from Bacillus subtilis are involved in a copper efflux pathway and both readily accommodate multinuclear Cu(I) clusters, overview
additional information
-
Escherichia coli survival is dependent on ATP7A expression in murine RAW-264.7 macrophages. Baterial survival is significantly increased in ATP7A-depleted cells compared with control cells, and copper pretreatment of ATP7A-depleted cells restores bactericidal activity to control levels, overview. Copper enhances the bactericidal activity of macrophages
additional information
in humans, mutations in the ATP7A and ATP7B genes cause improper function of these copper(I)-ATPases, leading to severe inheritable diseases that involve dysfunctional copper homeostasis, named Menkes and Wilson diseases, respectively
additional information
-
in humans, mutations in the ATP7A and ATP7B genes cause improper function of these copper(I)-ATPases, leading to severe inheritable diseases that involve dysfunctional copper homeostasis, named Menkes and Wilson diseases, respectively
additional information
-
mutation of ATP7A is involved in Menkes disease, a severe infantile-onset neurodegenerative disorder
additional information
-
mutation of ATP7A is involved in Menkes disease, a severe infantile-onset neurodegenerative disorder
additional information
-
mutation of ATP7A is involved in Menkes disease, a severe infantile-onset neurodegenerative disorder
additional information
-
mutation of the HP-motif and the Gly-rich sequence in the N-domain impairs ATP binding
additional information
mutations in ATP7B cause the Wilson disase, an autosomal recessive disorder
additional information
-
mutations in ATP7B cause the Wilson disase, an autosomal recessive disorder
additional information
-
mutations of ATP7A and ATP7B lead to the inherited disorders of Cu metabolism, Menkes and Wilson diseases. Disruption of ATP7B-mediated Cu export from liver hepatocytes into bile, and consequently liver and brain Cu accumulation. Elevation of Cu in vascular endothelial cells of the brains of MD patients indicates a role for this ATPase in Cu transport across the blood-brain barrier. ATP7A and ATP7B mediate resistance to anticancer drugs such as cis-diaminedichloroplatinum (II), i.e. cisplatin, by sequestration within intracellular compartments and potentially within the MBDs. Increased ATP7A/7B expression in a variety of clinical cancers and poorer survival rates following cisplatin-based chemotherapy, and between ATP7A upregulation and cancer metastasis
additional information
-
specific serine residues in ATP7A regulates its sub-cellular localization and hence function and will facilitate identification of the kinases and signaling pathways involved in regulating this pivotal copper transporter
additional information
-
specific serine residues in ATP7A regulates its sub-cellular localization and hence function and will facilitate identification of the kinases and signaling pathways involved in regulating this pivotal copper transporter. C-terminal MNK phosphorylation is essential for copper-responsive trafficking
Show AA Sequence and Transmembrane Helices (5570 entries)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
165000
64000
97000
additional information
64000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
64000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
97000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
97000
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
additional information
apparent mass of around 180-200 kDa in chloroplast and thylakoid membrane preparations
additional information
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apparent mass of around 180-200 kDa in chloroplast and thylakoid membrane preparations
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
?
-
x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
?
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x * 97000, splicing variant in cytosol and plasma membrane, SDS-PAGE, x * 64000, splicing variant in nucleus, SDS-PAGE
additional information
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peptide mapping and identification of putative Cu-responsive peptides, overview
additional information
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the amino-terminal domain of the enzyme contains six repeats of the copper binding motif GMTCXXC
additional information
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ATP7B from HEK-293 and Hep-G2 cells have different electrophoretic properties, ATP7B in Hep-G2 and HEK-293 cells differ in size, but not in post-translational modifications
additional information
analysis of the solution NMR structures of the N-domain of ATP7A in the ATP-free and ATP-bound forms, The structures consist of a twisted antiparallel six-stranded beta-sheet flanked by two pairs of alpha-helices, overview. Structure comparisons to Archeoglobus fulgidus CopA, overview
additional information
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analysis of the solution NMR structures of the N-domain of ATP7A in the ATP-free and ATP-bound forms, The structures consist of a twisted antiparallel six-stranded beta-sheet flanked by two pairs of alpha-helices, overview. Structure comparisons to Archeoglobus fulgidus CopA, overview
additional information
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peptide mapping and identification of putative Cu-responsive peptides, overview
additional information
small changes in individual sites, induced by copper binding or mutation, result in stabilization of distinct conformations of the entire N-ATP7B and altered exposure of sites for interactions with regulatory proteins. Structure modeling and molecular dynamics simulations, hydrogen bonding may play a role in the N-ATP7B folding and redox state, overview
additional information
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small changes in individual sites, induced by copper binding or mutation, result in stabilization of distinct conformations of the entire N-ATP7B and altered exposure of sites for interactions with regulatory proteins. Structure modeling and molecular dynamics simulations, hydrogen bonding may play a role in the N-ATP7B folding and redox state, overview
additional information
solution structure of the ATPbinding loop of ATP7B, and predictive model of the transduction domain, ATP loop, and associated transmembrane domains, overview
additional information
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solution structure of the ATPbinding loop of ATP7B, and predictive model of the transduction domain, ATP loop, and associated transmembrane domains, overview
additional information
solution structures of the A-domain of ATP7A and ATP7B, solved by heteronuclear NMR spectroscopy, and dynamics of the A-domain of ATP7A, structure modeling, overview. The catalytically important TGE loop protrudes from the structure ready for interaction with the phosphorilated site in the ATP-binding domain
additional information
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solution structures of the A-domain of ATP7A and ATP7B, solved by heteronuclear NMR spectroscopy, and dynamics of the A-domain of ATP7A, structure modeling, overview. The catalytically important TGE loop protrudes from the structure ready for interaction with the phosphorilated site in the ATP-binding domain
additional information
PcpA comtains a heavy-metal-associated domain, a P-type ATPase domain, and a haloacid dehalogenase-like hydrolase domain
additional information
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PcpA comtains a heavy-metal-associated domain, a P-type ATPase domain, and a haloacid dehalogenase-like hydrolase domain
additional information
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PcpA comtains a heavy-metal-associated domain, a P-type ATPase domain, and a haloacid dehalogenase-like hydrolase domain
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
additional information
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ATP7B in Hep-G2 and HEK-293 cells differ in size, but not in post-translational modifications
phosphoprotein
PAA1 is phosphorylated from ATP in the presence of monovalent metals (only CuCl2 and AgNO3). The presence of EGTA does not affect the phosphorylation levels
phosphoprotein
-
copper stimulates both trafficking and phosphorylation of ATP7A, identification of eight in vivo phosphorylation sites in the hamster ATP7A, all clustered within the N- and C-terminal cytosolic domains, C- and N-terminal phosphorylation sites, overview
phosphoprotein
-
two phosphorilation sites, phosphorilation is induced by copper
phosphoprotein
-
both MNK and WND are phosphorylated on serine residues, indicating a key role for one or more serine/threonine kinases for regulation of their trafficking and possibly function
phosphoprotein
-
cisplatin, i.e. cis-diamminedichloroplatinum or DDP, stimulates catalytic phosphorylation of ATP7B
phosphoprotein
-
ATP7B phosphorylation with ATP occurs with diphasic kinetics and is totally copper-dependent
phosphoprotein
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copper stimulates both trafficking and phosphorylation of ATP7A, identification of twenty in vivo phosphorylation sites in the human ATP7A, all clustered within the N- and C-terminal cytosolic domains, eight sites are copper-responsive and hence candidates for regulating copper-responsive trafficking or catalytic activity. A constitutively phosphorylated site is Ser1432, a copper-responsive phosphorylation site Ser1469. Other C-terminal phosphorylation sites are serine residues 1463, 1466, 1469, 1473, 1476 and 1480, C- and N-termninal phosphorylation sites, overview
phosphoprotein
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Ccc2 N-terminal phosphorylation may be coupled to the ATPase domain catalytic cycle. Protein kinase A phosphorylation site at Ser258 is located between MBD6 and the first transmembrane domain, Cu is predicted to promote Ser258 phosphorylation by increasing solvent accessibility of the region as a consequence of Cu-MBD interactions
phosphoprotein
the enzyme undergoes auto-phosphorylation on Asp627
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
electron cryomicroscopy of two-dimensional crystals, projection map at 7 A resolution with density peaks
crystallization and structure determination of the the apo- and phosphate-bound ATP-binding domain, hanging drop vapour diffusion method
crystallization trials are performed at 18 °C by vapor diffusion using the hanging-drop technique, crystal structure of the catalytic fragment of a Sulfolobus solfataricus P-type ATPase, CopB-B, is determined with a 2.6 A resolution.In CopB-B crystals, a bound sulfate anion is identified at the phosphate-binding location. In solution state bound phosphate can be readily displaced by orthovanadate at submillimolar concentration as well as by sulfate at millimolar concentration. It is possible to assign the structure of the sulfate-bound phosphorylation domain of CopB-B to a state related to an enzyme/phosphate intermediate state of the catalytic cycle
hangimg drop vapour diffusion method, 3D crystals of CopB-B, the 29 kDa catalytic ATP binding/phosphorylation domain are produced, which diffracted to a resolution of 2.2 A
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N923T
mutation in the Cvi allele in the tightly conserved domain N(x)6YN(x)4P, is a cause of dysfunction of the Cvi HMA5 allele
delM1-M54
a truncated CopB lacking the first 54 amino acids is constructed to characterize the N-terminal metal binding domain. This enzyme shows reduced ATPase activity (50% of wild type) but no changes in metal selectivity, ATP dependence, or phosphorylation levels
C1375S
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
C983A/C985A
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site-directed mutagenesis of CXC copper binding motif in the transmembrane copper site TM6, absence of alkali labile phosphoenzyme formation
D1027N
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site-directed mutagenesis of the P domain, absence of alkali labile phosphoenzyme formation
D1267V
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
E1064A
the mutation abolishes ATP binding to the N-domain. In the cell, neither the stability nor targeting of mutant E1064A to the trans-Golgi network differs significantly from the wild type enzyme
E1064K
located in the ATP-binding domain, marked impairment in copper transport function, identified as disease-causing mutation
E1173G
naturally occuring mutation in the ATP-binding loop of ATP7B, temperature-sensitive mutant, unable to complement the enzyme-deficient yeast mutant at 37°C, but complement the enzyme-deficient yeast mutant at 30°C
G1000R
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
G1101R
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
G1176E
naturally occuring mutation in the ATP-binding loop of ATP7B, intermediate mutant, unable to grow at 37°C without addition of copper or iron
G1287S
naturally occuring mutation in the ATP-binding loop of ATP7B, intermediate mutant, unable to grow under iron limitation
G853R
the mutation occurring in the A-domain of ATP7A affects the network of communication with the other domains of the enzyme
G860V
the mutation occurring in the A-domain of ATP7A destabilizes the fold of the domain
H1069Q
thermolabile mutant with impaired ATP binding. The mutation greatly destabilizes protein both in vitro and in cells
I1102T
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
I1148T
naturally occuring mutation in the ATP-binding loop of ATP7B, mild mutation, unable to grow under iron limitation
L1043P
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
L1083F
partial complementation at 30°C, severe deficit at 37°C observed, marked impairment in copper transport function found, identified as disease-causing mutation
L1373P
the mutant exhibits abnormal trafficking behavior, the half-life of the mutant protein is significantly shorter than that of the wild type enzyme
L1373R
the mutant exhibits abnormal trafficking behavior, the half-life of the mutant protein is significantly shorter than that of the wild type enzyme
L873R
the mutation occurring in the A-domain of ATP7A affects the network of communication within the domain
M1169V
partial complementation at 30°C and 37°C observed, partial reduction in ATP7B function´´, identified as disease-causing mutation
M672G/M674A/H676A/H677G/H682A/H683G
the mutant shows decreased affinity for copper. The mutations within the His/Met-rich segment Met672-Pro707 (HM-loop) do not prevent the ability of the enzyme to form a phosphorylated intermediate during ATP hydrolysis but inhibit subsequent dephosphorylation, a step associated with copper release
M687A/M692A
the mutant shows decreased affinity for copper. The mutations within the His/Met-rich segment Met672-Pro707 (HM-loop) do not prevent the ability of the enzyme to form a phosphorylated intermediate during ATP hydrolysis but inhibit subsequent dephosphorylation, a step associated with copper release
P1379
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
P1386S
-
naturally occuring mutation, a transition mutation of c.4156C>T in exon 22
R1228T
naturally occuring mutation in the ATP-binding loop of ATP7B, the mutant behaves similar to the wild-type enzyme, complements the enzyme-deficient yeast mutant
S1432A
-
site-directed mutagenesis of a constitutively phosphorylated site, mutation leads to mislocation of the enzyme in presence of Cu2+
S1469A
-
site-directed mutagenesis of a copper-responsive phosphorylation site, mutation leads to mislocation of the enzyme in presence of Cu2+
T1434M
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
T991M
naturally occuring mutation in the ATP-binding loop of ATP7B, mild mutation
T994I
-
naturally occuring mutation, a transition mutation of c.2981C>T in exon 15
V1106D
located in the ATP-binding domain, marked impairment in copper transport function, identified as disease-causing mutation
V1239G
naturally occuring mutation in the ATP-binding loop of ATP7B, deleterious mutation, unable to grow under iron limitation
X1466R
the mutant exhibits trafficking behavior similar to that observed for the wild type enzyme
S258A
the mutation abrogates all cAMP-dependent protein kinase-mediated phosphorylations of the enzyme (with an 8fold decrease in the burst of initial phosphorylation)
S258A/S971A
the mutations lead to an increase in its cAMP-dependent protein kinase-mediated global regulatory phosphorylation
S258D
the phosphomimetic mutant exhibits extremely slow phosphorylation
S971A
the mutation leads to a 100% increase in its cAMP-dependent protein kinase-mediated global regulatory phosphorylation
additional information
additional information
complementation assays of the ccc2 mutant of yeast using chimeric HMA5 proteins, a dysfunctional HMA5 allele is identified in Chisdra-2, which shows Cu sensitivity and low capacity of Cu translocation from roots to shoots, a unique amino acid substitution of Chisdra-2 occurs in another strictly conserved domain, CPC(x)6P, where the latter proline is replaced with leucine. The homozygous HMA5-KO line SALK_040252, carrying a T-DNA insertion at the first intron, shows hypersensitivity to Cu while showing similar growth to the wild type Col-0 in control solution
additional information
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construction of mutants with reduced heavy metal resistance, overview
additional information
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construction of mutants with reduced heavy metal resistance, overview
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additional information
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generation of gene BcCcc2 null mutants DELTABcCcc2, which show severely affected melanization, conidiation and the formation of sclerotia, phenotypes, overview. DELTABcCcc2 mutants are defective in infection of hosts through wounds
additional information
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generation of gene BcCcc2 null mutants DELTABcCcc2, which show severely affected melanization, conidiation and the formation of sclerotia, phenotypes, overview. DELTABcCcc2 mutants are defective in infection of hosts through wounds
-
additional information
CPA mutant analyzed, transmembrane transport function disabled by conversion of the transmembrane metal binding CPC motif to CPA
additional information
effects of Wilson disease-causing missense mutations on function and regulation of ATP7B, correlation between genetic defects with molecular functions of ATP7A and ATP7B and with clinical expression of these disorders
additional information
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apical/subapical MNK distribution of the MNK L1487-1488A mutant
additional information
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construction of a truncated version of ATPB7 lacking the first 33 amino acids, the mutant behaves like the full-length enzyme
additional information
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mutations of the first five N-terminal copper-binding sites of ATP7B do not inhibit the cisplatin-induced phosphorylation of ATP7B. In contrast, the deletion of the first four copper-binding sites abolishes the effect of cisplatin on the ATP7B activity
additional information
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transgenic C57BL/6J mice overexpressing the human ATP7A from the chicken beta-actin composite promoter CAG causes disturbances in Cu homeostasis, with depletion of Cu in some tissues, especially the heart. Cu exposure results in partial restoration of heart Cu concentrations in male transgenic mice. Despite the extended period of Cu exposure, Cu concentrations in the liver remain relatively unaffected, with a significant increase in male nontransgenic mice. In transgenic mice, expression levels of ATP7A and other Cu homeostasis proteins, as well as intracellular localization of ATP7A in various tissues are not significantly affected by Cu exposure
additional information
functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B
additional information
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functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B
additional information
mutations of copper-coordinating Cys to Ala in any metal-binding domains 2, 3, 4, or 6 change the N-ATP7B conformation and have distinct functional consequences, overview. The Cys-to-Ser mutation in MBD2 preserves the conformation and reduced state of N-ATP7B
additional information
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mutations of copper-coordinating Cys to Ala in any metal-binding domains 2, 3, 4, or 6 change the N-ATP7B conformation and have distinct functional consequences, overview. The Cys-to-Ser mutation in MBD2 preserves the conformation and reduced state of N-ATP7B
additional information
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ATP7A silencing by stable transfection of RAW-264.7 cells with ATP7A RNAi
additional information
gene pcpA silencing using RNA interference in strain GXCR leads to reduced PcpA activity and increased sensitivity of the mutant organism to Cu2+, Cd2+, Fe2+, and Ag+ compared to the wild-type, phenotype, overview
additional information
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gene pcpA silencing using RNA interference in strain GXCR leads to reduced PcpA activity and increased sensitivity of the mutant organism to Cu2+, Cd2+, Fe2+, and Ag+ compared to the wild-type, phenotype, overview
additional information
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gene pcpA silencing using RNA interference in strain GXCR leads to reduced PcpA activity and increased sensitivity of the mutant organism to Cu2+, Cd2+, Fe2+, and Ag+ compared to the wild-type, phenotype, overview
-
additional information
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ctpA disruption mutants show a drastic decrease in both cbb3 and caa3 oxidase activities. Inactivation of ctpA results also in a decrease in the amount of the nitrous oxide reductase, NosZ. This pleiotropic phenotype can be partially rescued by excess copper in the medium
additional information
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construction of the DELTAMBDCcc2 mutant lacking the N-terminus. In vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2, however, M1 or M2, expressed in place of the metallo-chaperone Atx1, are not as efficient as Atx1 in delivering copper to the Ccc2 N-terminus. But when the Ccc2 N-terminus is truncated in mutant DELTAMBDCcc2, these independent metal-binding domains behave like functional metallo-chaperones in delivering copper to another copper-binding site in Ccc2. Both M1 and M2, when expressed as independent cytosolic proteins, are able to bind copper in the cytosol and transfer this metal to a copper-binding site in Ccc2, out of the N-terminus
additional information
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yeast deficient in Ccc2 function cannot survive when iron is limiting, functional complementation by expression of wild-type human ATP7B
additional information
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yeast deficient in Ccc2 function cannot survive when iron is limiting, functional complementation by expression of wild-type human ATP7B
-
additional information
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construction of the DELTAMBDCcc2 mutant lacking the N-terminus. In vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2, however, M1 or M2, expressed in place of the metallo-chaperone Atx1, are not as efficient as Atx1 in delivering copper to the Ccc2 N-terminus. But when the Ccc2 N-terminus is truncated in mutant DELTAMBDCcc2, these independent metal-binding domains behave like functional metallo-chaperones in delivering copper to another copper-binding site in Ccc2. Both M1 and M2, when expressed as independent cytosolic proteins, are able to bind copper in the cytosol and transfer this metal to a copper-binding site in Ccc2, out of the N-terminus
-
additional information
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construction of the DELTAMBDCcc2 mutant lacking the N-terminus. In vivo Atx1-M1 or Atx1-M2 interactions activate Ccc2, however, M1 or M2, expressed in place of the metallo-chaperone Atx1, are not as efficient as Atx1 in delivering copper to the Ccc2 N-terminus. But when the Ccc2 N-terminus is truncated in mutant DELTAMBDCcc2, these independent metal-binding domains behave like functional metallo-chaperones in delivering copper to another copper-binding site in Ccc2. Both M1 and M2, when expressed as independent cytosolic proteins, are able to bind copper in the cytosol and transfer this metal to a copper-binding site in Ccc2, out of the N-terminus
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme is truncated by 5 of the six metal binding domains and endowed with an N-terminal histidine-tag for affinity purification, recombinantly expressed in Escherichia coli and reconstituted into proteoliposomes
fusion protein of glutathione-S-transferase and Wilson-disease protein expressed in Escherichia coli
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purification of three different soluble domains of the protein (CopB-A), CopB-B (ATP binding/phosphorylation domain), and CopB-C (cation binding domain)
recombinant His-tagged ATP7A or MNK from Escherichia coli strain BL21(DE3)
recombinant myc-tagged ATP7B is isolated from the microsomal fraction of COS-1 cell homogenates
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
ATP7A is located on Xq13.2-13.3, spans about 150 kb and has 23 exons, ATP7B is located on chromosome 13, spans about 80 kb and contains 21 exons, ATP7A and ATP7B expression pattern analysis, overview
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ATP7B expression in Sf9 insect cells, epitope-tagged ATP7B-HA56 variant generated and expressed in oocytes of Xenopus laevis, N-terminal and C-terminal deletions included to analyze delivery of ATP7B-HA56 from the membrane, wild-type ATP7B used as a control
cloning of the DNA segment coding for the N-terminal copper-binding region into a GST pGEX-6P-2 vector
co-expression of Atx1 and Ccc2 mutants in an atx1Dccc2D yeast strain
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construction and expression of the fusion protein of glutathione-S-transferase and Wilson-disease protein and expression in Escherichia coli
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DNA sequence and genetic structure analysis of ATP7B from renal and hepatic tissue and comparison, recombinant ATP7B expressed in renal cells is similar to hepatic protein in size and trafficking, ATP7B lacking the exon 1 sequence shows cell-specific trafficking in polarized renal and hepatic cells, overview
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Drosophila transformation vector pW8 used, generation of transgenic lines and construction of a EYFP-DmATP7 fusion protein for localization studies described
enzyme is expressed using pGEX-4T-2, subcloned into pGEX-6P-2 and expressed in Escherichia coli strain BL21
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expressed in Saccharomyces cerevisiae copper-transporting ATPase Ccc2-deficient cells
-
expressed in Sf9 insect cells
expression in Escherichia coli
expression in Escherichia coli of the N-domain fused with a chitin-binding domain, several N-domain mutants cloned using the same procedure
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expression of a chimeric metal bidnding sequence with the Menkes disease protein carrying the binding motif of bacterial Hg(II) binding protein MerP. This chimeric protein shows differences in structure and the dynamics of the binding site that may account for metal specificity
expression of ATP7B in Spodoptera frugiperda Sf9 cell membranes via baculovirus transfection, overexpression of ATP7B in ovary cells causes increased cellular resistance to cisplatin, a chemotherapeutic agent
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expression of Menkes disease protein with an N-terminal Glu-Glu tag in Sf9 cells
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expression of the DNA sequence encoding MNK3, corresponding to amino acids 275-352 of ATP7A in Escherichia coli strain BL21 (DE3)pLysS. Introduction of a C-terminal expression tag including His6 to ease purification
expression of three different soluble domains of the protein (CopB-A (phosphatase domain), CopB-B, and CopB-C) in Escherichia coli
expression of wild type and several mutants in Saccharomyces cerevisiae and CHO cells
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expression of wild-type and mutant ATP7B ATP binding loops in ccc2-deficient Saccharomyces cerevisiae strain
expression of wild-type and mutant myc-tagged ATP7Bs in COS1 cells using an adenoviral vector
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gene ATP7A, genetic mapping and expression analysis of splicing variants, overview
gene ATP7A, overexpression of His-tagged ATP7A or MNK in Escherichia coli strain BL21(DE3), overexpression of the soluble nucleotide-binding domain of MNK protein, comprising amino acids 1051-1231
gene ATP7B, expression in HEK-293 cells and in mesenchymal stem cells derived from bone marrow, viability of these cells is significantly enhanced after ATP7B transduction, expression analysis, overview
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gene BcCcc2, DNA and amino acid sequence determination and analysis, phylogenetic analysis
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gene CCC", DNA and amino acid sequence determination and analysis, phylogenetic analysis
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gene pcpA, cDNA and amino acid sequence determination and analysis, quantitative real-time PCR expression analysis and sequence comparison, overview
infection of Sf9 cells with baculoviral constructs encoding wild-type ATP7B and a mutant variant unable to transport copper
mutant variants of ATP7B expressed in protease-deficient Saccharomyces cerevisiae strain BJ2168 and in ccc2 and fet3 mutant strains lacking functional CCC2 and FET3 genes
overexpression of ATP7A and ATP7B in Me32a cells mediating resistance to bioavailable platinum analogue agents DDP and JM118, expression of ATP7A and ATP7B in the two-hydrid expression system for interaction analysis
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rescue and correction of the Cu accumulation defect by expression of wild type MNK in non-polarized BHK cells
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the catalytic fragment CopB-B is expressed in Escherichia coli
the enzyme is truncated by 5 of the six metal binding domains and endowed with an N-terminal histidine-tag for affinity purification. This construct is able to functionally complement a yeast strain defective in its native copper ATPase CCC2. Expression in Escherichia coli
gene ATP7A, genetic mapping and expression analysis of splicing variants, overview
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gene ATP7A, genetic mapping and expression analysis of splicing variants, overview
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
COMM-domain-containing 1 knockdown reduces the expression of Atp7b, and abolishes the relocation of Atp7b back from the periphery to the trans-Golgi network membrane
iron deprivation induces all three splicing variants 5-7fold
isoform PAA2 protein abundance decreases significantly and specifically when Cu in the media is increased. Copper addition does not affect PAA2 transcript levels, but stability of the PAA2 protein is decreased in plants grown with elevated copper levels
PAA2 protein abundance is significantly increased in paa1 mutants, in which the copper content in the chloroplast is half of that of the wild-type, due to impaired copper import into the organelle. In a pc2 insertion mutant, which has strongly reduced plastocyanin expression, the PAA2 protein levels are low regardless of copper addition to the growth media
synthesized at low levels under standard growth conditions (i.e. under copper limitation), and the expression levels increases after addition of copper
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
medicine
drug development
ATP7A shown to confer resistance to various anticancer agents on cancer cells, discussed as a good index of drug resistance in clinical colon cancers
drug development
review on transport mechanisms of platinum-based antitumor agents
medicine
the overexpression of ATP7B in hepatocellular carcinoma might be associated with unfavorable clinical outcome in patients treated with cisplantin-based chemotherapy. Analysis of ATP7B expression might be clinically relevant for the choice of therapy
medicine
molecular mechanisms of copper deficiency (Menkes disease) or copper overload (Wilson disease)
medicine
studies on copper deficiency during pregnancy, Menkes and Wilson disease
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EXTERNAL LINKS (specific for EC-Number 7.2.2.9)
Transporter Classification Database (TCDB): 3.A.3.5.12, 3.A.3.5.10
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Release 2023.1 (January 2023)
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