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Information on EC 5.6.1.6 - channel-conductance-controlling ATPase
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5.6.1.6 channel-conductance-controlling ATPaseIUBMB Comments
ABC-type (ATP-binding cassette-type) ATPase, characterized by the presence of two similar ATP-binding domains. The enzyme is found in animals, and in humans its absence brings about cystic fibrosis. Unlike most of the ABC transporters, chloride pumping is not directly coupled to ATP hydrolysis. Instead, the passive flow of anions through the channel is gated by cycles of ATP binding and hydrolysis by the ATP-binding domains. The enzyme is also involved in the functioning of other transmembrane channels.
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Word Map
- 5.6.1.6
- airway
- pulmonary
- camp
- epithelium
- pancreatic
-
gate
-
gating
- forskolin
- bronchial
-
transepithelial
-
nasal
-
deltaf508
- na+
-
f508del
-
mucus
-
camp-dependent
-
short-circuit
-
blocker
-
nucleotide-binding
- deferens
-
patch-clamp
-
caucasian
-
cotransporter
- bicarbonate
- glibenclamide
-
ussing
-
mucociliary
-
camp-activated
-
non-cf
- infertility
-
electrolyte
-
camp-stimulated
-
single-channel
-
calu-3
-
camp-regulated
-
electrogenic
- bumetanide
-
outwardly
-
forskolin-stimulated
-
current-voltage
- bronchiectasis
- amiloride
-
inside-out
- azoospermia
-
cell-attached
-
amiloride-sensitive
- ibmx
- trypsinogen
-
spink1
- medicine
-
meconium
The enzyme appears in viruses and cellular organisms
Reaction Schemes
+
+
closed Cl- channel
=
+
+
open Cl- channel
Synonyms
cystic fibrosis transmembrane conductance regulator, cystic fibrosis transmembrane regulator, cftr channel, cftr cl- channel, cystic fibrosis conductance regulator, abcc7, epithelial basolateral chloride conductance regulator, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ABCC7
CFTR
cystic fibrosis transmembrane conductance regulator
cystic-fibrosis membrane-conductance protein
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EC 3.6.3.49
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-
formerly
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transmembrane domains of cystic fibrosis transmembrane conductance regulator
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transmembrane domains of cystic fibrosis transmembrane conductance regulator channel
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additional information
CFTR
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-
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CFTR
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654579, 654722, 655993, 656248, 671252, 672380, 672639, 673218, 673336, 673494, 674413, 674414, 675114, 675175, 675176, 675188, 695466, 696099, 697823, 697846, 698081, 698802, 698823, 699175, 699294, 699786, 699787, 700093, 700104, 700296, 700618, 700965, 712113, 712847, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395
CFTR
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cystic fibrosis transmembrane conductance regulator
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-
-
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cystic fibrosis transmembrane conductance regulator
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654579, 654722, 655993, 656248, 672380, 672639, 673218, 673336, 673494, 674413, 674414, 675114, 675175, 675176, 675188, 695466, 696099, 697823, 697846, 698081, 698802, 698823, 698868, 699175, 699787, 700093, 700104, 700296, 700618, 700965, 712113, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395
cystic fibrosis transmembrane conductance regulator
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additional information
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CFTR is a member of the ATP-binding cassette (ABC) transporter superfamily
additional information
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CFTR is a member of the ATP-binding cassette, ABC, transporter superfamily
additional information
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the enzyme belongs to the ATP-binding cassette transporter superfamily
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
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-
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
asymmetric motion of the nucleotide binding domains 1 and 2 during channel gating. Opening of the channel is initiated by ATP at the nucleotide-binding domain 2 site, whereas separation of the nucleotide-binding domain dimer at the nucleotide-binding domain 1 site constitutes the rate-limiting step in channel closing
ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
the conformation of nucleotide-binding domain 1 changes before that of nucleotide-binding domain 2 during channel opening. Nucleotide-binding domain dimerization does not proceed by a symmetric tweezer-like motion, but instead in an asymmetric fashion led by nucleotide-binding domain1
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
the conformation of nucleotide-binding domain1 changes before that of nucleotide-binding domain 2 during channel opening. Nucleotide-binding domain dimerization does not proceed by a symmetric tweezer-like motion, but instead in an asymmetric fashion led by nucleotide-binding domain1
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
ATP binding, conformational changes, and ATPase and channel activity reaction mechanism, overview
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
the structure of the CFTR channel pore is highly asymmetric with a narrower extracellular entrance and a dilating conformational change of the extracellular entrance is associated with the channel transition to a nonhydrolytic, locked-open state
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
upon channel opening, the wide cytoplasmic vestibule tightens and the pore-lining TM12 rotates along its helical axis
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ATP + H2O + closed Cl- channel = ADP + phosphate + open Cl- channel
regulation of CFTR activation by R domain phosphorylation followed by ATP binding at the nucleotide-binding domain-1 site enables the cycling mechanism to proceed. ATP catalysis at the catalytically active nucleotide?binding domain-2 is sufficient to drive the gating cycle, CFTR gating mechanism proceeds in 4 steps, detailed overview. The enzyme being a functional channel adapts the ATP switch gating mechanism designed for transporters, ATP Switch model analysis
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of phosphate bond
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transmembrane transport
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SYSTEMATIC NAME
IUBMB Comments
ATP phosphohydrolase (channel-conductance-controlling)
ABC-type (ATP-binding cassette-type) ATPase, characterized by the presence of two similar ATP-binding domains. The enzyme is found in animals, and in humans its absence brings about cystic fibrosis. Unlike most of the ABC transporters, chloride pumping is not directly coupled to ATP hydrolysis. Instead, the passive flow of anions through the channel is gated by cycles of ATP binding and hydrolysis by the ATP-binding domains. The enzyme is also involved in the functioning of other transmembrane channels.
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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
5-methyl-dCTP + H2O + closed Cl- channel
5-methyl-dCDP + phosphate + open Cl- channel
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-
-
?
7-methyl-GTP + H2O + closed Cl- channel
7-methyl-GDP + phosphate + open Cl- channel
-
-
-
?
CTP + H2O + closed Cl- channel
CDP + phosphate + open Cl- channel
-
-
-
?
dATP + H2O + closed Cl- channel
dADP + phosphate + open Cl- channel
-
-
-
?
dCTP + H2O + closed Cl- channel
dCDP + phosphate + open Cl- channel
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-
-
?
dGTP + H2O + closed Cl- channel
dGDP + phosphate + open Cl- channel
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-
-
?
dTTP + H2O + closed Cl- channel
dTDP + phosphate + open Cl- channel
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-
-
?
dUTP + H2O + closed Cl- channel
dUDP + phosphate + open Cl- channel
-
-
-
?
TTP + H2O + closed Cl- channel
TDP + phosphate + open Cl- channel
-
-
-
?
UTP + H2O + closed Cl- channel
UDP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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654515, 654536, 654579, 654722, 655993, 656427, 674414, 675176, 699787, 700296, 700965, 719248, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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chloride channel
210420, 210421, 210422, 210423, 210424, 210425, 210426, 210427, 210428, 210429, 210430, 210431, 210432, 210433, 210434, 210435
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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coupling between ATP hydrolysis and chloride channel gating
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a multiion-pore
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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dysfunction of CFTR causes the genetic disease cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the chloride channel is regulated by phosphorylation of the R domain and ATP hydrolysis at two nucleotide binding domains
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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transport of Cl-, I-, and with lower efficiency Br- and F-
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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syntaxin 1A limits the functional activities of normal and disease-associated forms of the chloride channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR appears to be important both as a HCO3- conductance and also in some way as a direct or indirect regulator of adjacent anion exchange, e.g. as a source of luminal Cl- that may exchange for cellular HCO3- and/or as a means of keeping cellular Cl- concentration low enough that the anion exchanger operates as an HCO3- secretion mechanism
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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enzyme is regulated by cAMP
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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small-conductance chloride channel, direct coupling between cellular ATP levels and chloride channel activity may be an adaptive mechanism to protect the tissue from damage resulting from excessive energy depletion
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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can function as a chloride-selective anion channel, may also play a role in regulation of the membrane vesicle trafficking and fusion, acidification of organelles and transport of small anions
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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mediates transepithelial salt and lipid movement in the apical membrane of epithelia
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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malfunction of CFTR causes cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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malfunction of CFTR causes cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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ATPase that functions as a Cl- channel in which bursts of opening separate relatively long inburst closed times. ATP must bind at both catalytic sites before a CFTR channel can open. The opening is rate limiting by a slow step after binding that is rate limited by a slow step after binding that is sensitive to the structure of the polyphosphate chaIN: No further nucleotide binding to the open channel. Hydrolysis at nucleotide binding domain 2 preceds normal rapid channel closing. The integrity of the nucleotide binding domain 1 Walker A motif, and nucleotide bound there, influences the rate of exit from locked-open burst states
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme functions in vivo as a cAMP-activated chloride channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme normally functions as a phosphorylation-regulated chloriode channel on the apical surface of epithelial cells, and lack of this function is the primary cause for the fatal disease cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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protein kinase A phosphorylates a group of R-domain serine residues in nucleotide binding domain 1. This causes the fusion protein to dimerize, to exhibit cooperative ATP binding and hydrolysis, and to be subject to regulation by nucleotide binding domain 2
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the NBF1+R segment (nucleotide binding domain 1 and regulatory domain) has the capacity to catalyze ATP hydrolysis in the absence of a fusion partner
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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ATP binding induces a modest conformational change in the sixth transmembrane segment, and this conformational change is coupled to the gating mechanism that regulates ion conduction
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR acts as an ATP-dependent chloride channel. CFTR channel activity evolved, at least in part, by converting the conformational changes associated with binding and hydrolysis of ATP
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR functions as an ATP-gated Cl- channel that is critical for proper hydration of the mucosal layer that lines lung airways. Individuals who inherit two mutant forms of CFTR have exceedingly viscous mucous and, due to chronic lung infections, develop cystic fibrosis and often die from lung failure
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
CFTR is a chloride channel whose dysfunction causes cystic fibrosis. The two intracellular nucleotide-binding domains of CFTR control the opening and closing of the channel, structure modelling of the CFTRs NBD1-NBD2 complex using the NBD crystal structures, overview
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a Cl- channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR shares a common molecular mechanism with other members of the ATP-binding cassette superfamily. CFTR gating is regulated by protein kinase A-mediated phosphorylation and by interaction with ATP
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme also shows ion channel activity
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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analysis of the dynamic events involved in the allosteric regulation of CFTR function, role of ATP hydrolysis in CFTR function, CFTR channel gating is a reversible thermally driven process with all structural reorganization in the binding site(s) completed prior to channel opening, requirement for nucleotide binding for channel opening, overview
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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ATP binding, at one or both nucleotide binding sites, occurs on closed channels and is required for channel opening. ATP binds to partial binding sites on the surface of the two nucleotide binding sites, NBDs, which then associate to form a NBD dimer, with complete composite catalytic sites now buried at the interface. After ATP binding, formation of a tight NBD1/NBD2 dimer is coupled to conformational changes in the transmembrane domains opening the diffusion pathway for anions. Hydrolysis at the consensus site allows fast channel closure, controlled by NBD dimerization, overview
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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binding mode of ATP in the CFTR nucleotide-binding domain NBD1-NBD2 dimer, organisation of the ATP-binding sites in CFTR involving Walker A and B motifs, and the signature sequence LSGGQ, and conformational changes of the CFTR Cl- channel during channel gating, overview
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
binding mode of ATP in the CFTR nucleotide-binding domain NBD1-NBD2 dimer: residue W401 of NBD1 forms ring-ring stacking with the adenine ring of ATP, residues at the NBD2 site that exhibit hydrogen bonding with the second ATP molecule include G1247, S1248, K1250, S1251, T1252 of the Walker A motif of NBD2, Q1291 of the Q-loop of NBD2, T547, S549, and G551 of the signature motif of NBD1. D1370 and E1371 of the Walker B of NBD2 coordinate MgATP, while Y1219 of NBD2 coordinates the adenine ring of ATP through ring-ring stacking
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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Mg2+-dependent ATP occlusion at the first nucleotide-binding domain, NBD1, of CFTR does not require the second, NBD2. ATP binding to the first and second NBDs of CFTR are bivalent-cation-independent and -dependent steps, respectively
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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stable binding of ATP at nucleotide binding site NBD1 and binding and hydrolysis of ATP at NBD2, together with R domain phosphorylation, may alter allosteric interactions between these domains and impact the channel gating cycle
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the Walker A and the Walker B motifs together with the signature sequence LSGGQ form the ATP-binding pocket upon dimerization of the two nucleotide-binding domains in a head-to-tail configuration
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
ATP binding gates open enzyme CFTR by an allosteric mechanism, ATP binding biases the equilibrium toward the CFTR open state but is not absolutely required for channel opening
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
using inside-out membrane patches from HeLa cells recombinantly and transiently expressing either wild-type or mutant enzyme CFTR
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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ATP in form of MgATP2-
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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chloride channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme is an ATP-binding cassette transporter that functions as a chloride channel. Channel gating occurs through ATP binding in an nucleotide-binding domain 1-nucleotide-binding domain 2 nucleotide sandwich that forms upon displacement of nucleotide-binding domain 1 regulatory segments
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a Cl- channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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chloride channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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EBCR is involved in hormone-regulated chloride reabsorption
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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ATPase activity is much higher at NBD1 than NBD2 of CFTR, ATPase activity is not strictly required for its channel activity
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
shark
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chloride channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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anion permeability sequence: Br- = I-, Cl-
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
chloride channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
sequence differences in the first membrane-spanning domains in human and Xenopus sp. are responsible for the differences in the permeation properties of human and Xenopus CFTR, the first extracellular loop influences channel gating
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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anion permeability sequence: Br- = Cl-, I-
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-
?
GTP + H2O + closed Cl- channel
GDP + phosphate + open Cl- channel
-
-
-
?
additional information
?
-
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the cystic fibrosis transmembrane conductance regulator normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cell, and lack of this function is the primary cause for the fatal disease cystic fibrosis
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-
?
additional information
?
-
CFTR protein channel requires phosphorylation by PKA before they can be opened by ATP, close upon ATP removal, and are activated half-maximally by 0.05 mM ATP
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-
?
additional information
?
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the isolated nucleotide-binding domains exhibit adenylate kinase activity, while the full-length purified and reconstituted protein functions as a ATPase
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?
additional information
?
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a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator results in abnormal electrolyte permeability in various exocrine epithelia causing cystic fibrosis, one of the most common lethal autosomal recessive disorders in Caucasian populations
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?
additional information
?
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-
cAMP-dependent on for Cl- conductance, no concurrent activation of K+ conductance. CFTR defects abolishes beta-adrenergic response of sweat gland and sweating in cystic fibrosis, but not cholinergic sweating, overview
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-
?
additional information
?
-
-
cytosolic 70-kDa heat shock protein and endoplasmic reticulum-localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and posttranslational degradation of CFTR
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-
?
additional information
?
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-
enzyme defects or inhibition lead to cystic fibrosis
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-
?
additional information
?
-
-
neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease
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-
?
additional information
?
-
-
the cystic fibrosis transmembrane conductance regulator is a unique ATP-binding cassette ion channel mutated in patients with cystic fibrosis
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-
?
additional information
?
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-
the enzyme acts as an ion channel, e.g. transporting chloride and the anionic cysteine-reactive reagents methanesulfonate sodium (2-sulfonatoethyl)methanesulfonate, organic mercurial 4-chloromercuriphenylsulfonic acid, and the permeant anion Au(CN)2-, but only in activated status, in nonactivated channels some ion selectivity mechanism exists to exclude anions yet permit cations into the channel pore from the extracellular solution. Activation of CFTR channels involves a conformational change in the pore that removes a strong selectivity against anion entry from the extracellular solution
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-
?
additional information
?
-
-
the enzyme performs Cl- conductance. Chaperones Hsp70 and Hsp90 associate equally with wild-type and mutant DELTAF508 CFTR, whereas nearly twice as much of the Hsp90 cochaperone, Aha1, associates with mutant DELTAF508 CFTR
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-
?
additional information
?
-
-
wild-type CFTR functions as a cAMP-activated chloride channel that has an important role in ion transport across the apical surfaces of secretory epithelia, also requiring caveolin-1 spatially associated to CFTR. Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa in lungs. The cells reaction involves the rapid formation of detergent-resistant membrane microdomains, i.e. lipid rafts, containing CFTR. Enzyme defects lead to defective innate immunity and susceptibility to chronic lung infection with Pseudomonas aeruginosa in cystic fibrosis patients, overview
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-
?
additional information
?
-
-
an ATPase cycle involving formation and dissociation of tight nucleotide binding dimers drives the cyclical conformational changes in the transmembrane domains resulting in uphill allocrite transport, via ATP binding, tight NBD dimerization, hydrolysis, loss of the gamma-phosphate, and opening of the NBD-NBD interface
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-
?
additional information
?
-
-
mechanism of action of small molecules that modulate CFTR channel gating
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-
?
additional information
?
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-
the enzyme shows ATPase and chloride channel activities
-
-
?
additional information
?
-
-
a stable binding of ATP to NBD2 is required forthe normal, fast gating cycle of CFTR channel, and instability of ATP binding frequently halts the CFTR gating cycle in the open state presumably through a slowdown of ATP hydrolysis at NBD2
-
-
?
additional information
?
-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
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-
?
additional information
?
-
-
cystic fibrosis transmembrane conductance regulator (CFTR) channels have ATPase and adenylate kinase activity. In presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The enzyme interacts with AMP in an ATP-dependent manner
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-
?
additional information
?
-
two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
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-
?
additional information
?
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two salt bridges in human CFTR chloride ion channels, Arg352-Asp993 and Arg347-Asp924, are required for normal channel function, cooperation mode to maintain the open pore architecture of the enzyme, overview. Arg347 not only interacts with Asp924 but also interacts with Asp993. Arg347 forms a salt bridge with Asp924 but does not stabilize the full open state. The tripartite interaction Arg347-Asp924-Asp993 mainly contributes to maintaining a stable s2 open subconductance state. The Arg352-Asp993 salt bridge, in contrast, is involved in stabilizing both the s2 and full (f) open conductance states, with the main contribution being to the f state. The s1 subconductance state does not require either salt bridge
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?
additional information
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in the presence of ATP and physiologically relevant concentrations of AMP, the enzyme exhibits adenylate kinase activity, converting ATP and AMP into 2 ADP and vice versa. The interaction of nucleotide triphosphate with the enzyme at ATP-binding site 2 is required for this activity. ATP and AMP interact with separate binding sites but mutually influence their interaction with the ABC adenylate kinase CFTR, the active center of the adenylate kinase comprises ATP-binding site 2
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?
additional information
?
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enzyme defects or inhibition lead to cystic fibrosis
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?
additional information
?
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neither channel activation nor inhibition influence the pH in recycling endosomes nor immature phagosomes. Perturbations of the endo-lysosomal organelles pH homeostasis cannot be linked to the etiology of the cystic fibrosis lung disease, effect of CFTR deficiency in genetically matched respiratory epithelia and alveolar macrophages, overview. CFTR-independent endosomal and phagosomal acidification occurs in RAW macrophages
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?
additional information
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ATP gates ovine CFTR with greater affinity and efficacy than human CFTR
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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 + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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-
654515, 654536, 655993, 699787, 749931, 749957, 750068, 750275, 750278, 750279, 750284, 750504, 750505, 750519, 751062, 751065, 751395
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
-
-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
coupling between ATP hydrolysis and chloride channel gating
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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syntaxin 1A limits the functional activities of normal and disease-associated forms of the chloride channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR appears to be important both as a HCO3- conductance and also in some way as a direct or indirect regulator of adjacent anion exchange, e.g. as a source of luminal Cl- that may exchange for cellular HCO3- and/or as a means of keeping cellular Cl- concentration low enough that the anion exchanger operates as an HCO3- secretion mechanism
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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enzyme is regulated by cAMP
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
small-conductance chloride channel, direct coupling between cellular ATP levels and chloride channel activity may be an adaptive mechanism to protect the tissue from damage resulting from excessive energy depletion
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
can function as a chloride-selective anion channel, may also play a role in regulation of the membrane vesicle trafficking and fusion, acidification of organelles and transport of small anions
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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CFTR is a conductance regulator as well as a Cl- channel, CFTR regulates other ion channel proteins
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
mediates transepithelial salt and lipid movement in the apical membrane of epithelia
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
malfunction of CFTR causes cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
ATPase that functions as a Cl- channel in which bursts of opening separate relatively long inburst closed times. ATP must bind at both catalytic sites before a CFTR channel can open. The opening is rate limiting by a slow step after binding that is rate limited by a slow step after binding that is sensitive to the structure of the polyphosphate chaIN: No further nucleotide binding to the open channel. Hydrolysis at nucleotide binding domain 2 preceds normal rapid channel closing. The integrity of the nucleotide binding domain 1 Walker A motif, and nucleotide bound there, influences the rate of exit from locked-open burst states
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme functions in vivo as a cAMP-activated chloride channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme normally functions as a phosphorylation-regulated chloriode channel on the apical surface of epithelial cells, and lack of this function is the primary cause for the fatal disease cystic fibrosis
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR acts as an ATP-dependent chloride channel. CFTR channel activity evolved, at least in part, by converting the conformational changes associated with binding and hydrolysis of ATP
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR functions as an ATP-gated Cl- channel that is critical for proper hydration of the mucosal layer that lines lung airways. Individuals who inherit two mutant forms of CFTR have exceedingly viscous mucous and, due to chronic lung infections, develop cystic fibrosis and often die from lung failure
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
CFTR is a chloride channel whose dysfunction causes cystic fibrosis. The two intracellular nucleotide-binding domains of CFTR control the opening and closing of the channel, structure modelling of the CFTRs NBD1-NBD2 complex using the NBD crystal structures, overview
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
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-
?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR shares a common molecular mechanism with other members of the ATP-binding cassette superfamily. CFTR gating is regulated by protein kinase A-mediated phosphorylation and by interaction with ATP
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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the enzyme also shows ion channel activity
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
the enzyme is an ATP-binding cassette transporter that functions as a chloride channel. Channel gating occurs through ATP binding in an nucleotide-binding domain 1-nucleotide-binding domain 2 nucleotide sandwich that forms upon displacement of nucleotide-binding domain 1 regulatory segments
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
-
CFTR is a Cl- channel
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?
ATP + H2O + closed Cl- channel
ADP + phosphate + open Cl- channel
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EBCR is involved in hormone-regulated chloride reabsorption
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?
additional information
?
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the cystic fibrosis transmembrane conductance regulator normally functions as a phosphorylation-regulated chloride channel on the apical surface of epithelial cell, and lack of this function is the primary cause for the fatal disease cystic fibrosis
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?
additional information
?
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a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator results in abnormal electrolyte permeability in various exocrine epithelia causing cystic fibrosis, one of the most common lethal autosomal recessive disorders in Caucasian populations
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?
additional information