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Information on EC 3.4.23.B24 - signal peptide peptidase
for references in articles please use BRENDA:EC3.4.23.B24preliminary BRENDA-supplied EC number
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EC Tree
3.4.23.B24 signal peptide peptidaseSpecify your search results
Word Map
- 3.4.23.B24
-
aspartyl
-
presenilins
-
intramembrane-cleaving
- gamma-secretase
- sppl2a
- medicine
-
gxgd-type
-
spp-mediated
- bri2
- i-clips
-
presenilin-like
-
site-2
- pharmacology
- analysis
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
signal peptide peptidase, sppl2b, signal peptide peptidase-like 2b, signal peptide peptidase-like 3, minor histocompatibility antigen h13, signal peptide peptidase-like 2c, aspartic intramembrane protease, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ANID_08681
aspartic intramembrane protease
hSPP
signal peptide peptidase-like 2a
signal peptide peptidase-like 2C
SPP
SPP1
SppA
SPPL2a
SPPL2b
SPPL2c
UMAG_02729
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
intramembrane cleavage of signal peptides
-
-
-
-
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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
Bri2 + H2O
?
release of an intracellular peptide
-
-
?
myc-prolactin-PP-Flag peptide + H2O
?
human signal peptide peptidase substrate
migration of the fragments that are cleaved in SDS-PAGE is identical in size to the fragments produced by human signal peptide peptidase
-
?
protein NSm precursor + H2O
mature NSm protein + NSm domain I signal peptide
-
a Bunyamwera orthobunyavirus glycoprotein precursor-derived nonstructural protein
-
-
?
unfolded protein response regulator XBP1u + H2O
?
-
-
cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an signal peptide peptidase substrate through specific sequence features
-
?
XBP1 + H2O
?
-
the isolated XBP1u hydrophobic region and the isolated transmembrane domain (TDM) region with N-terminal flanking residues of the enzyme interact, positional effect of di-glycine motifs of XBP1u on SPP-catalyzed turnover. Enzyme activity with diverse substrate mutants, overview
-
-
?
CD74 + H2O
?
-
although SPPL2b can cleave CD74 when overexpressed, it does not appear contribute to CD74 NH2-terminal fragment turnover
-
-
?
CD74 + H2O
?
-
SPPL2a cleaves CD74 and contributes to CD74 NH2-terminal fragment turnover
-
-
?
CD74 NTF + H2O
?
release of intracellular peptide
-
-
?
Fba + H2O
?
-
a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF
-
-
?
Fba + H2O
?
-
a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive
-
-
?
Fba + H2O
?
-
a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF. SPPL2b reduced levels of the intact FBA substrate by over 90%, which is higher than the activity of other SPPs
-
-
?
Fba + H2O
?
-
a recombinant substrate consisting of the amino-terminus of BRI2 fused to amyloid beta 1-25, with a K16A mutation incorporated to prevent potential alpha-secretase cleavage that would preclude ELISA based detection of the released COOH-terminal fragment. The enzyme shows different cleavage site specificity compared to other signal peptide peptidases, the cleavage may be processive. hSPP processes of FBA resulting in a gap between the carboxyl end of the ICD and the NH2-terminus of the CTF. Enzyme pSPP may have more than one cleavage site
-
-
?
heme oxygenase-1 + H2O
?
-
-
signal peptide peptidase SPP catalyzes the intramembrane cleavage of heme oxygenase-1. Two adjacent intramembrane cleavage sites are located after S275 and F276 within the trans membrane segment
-
?
protein Gc precursor + H2O
mature Gc protein + NSm domain V signal peptide
-
a Bunyamwera orthobunyavirus glycoprotein precursor-derived nonstructural protein
-
-
?
protein Gc precursor + H2O
mature Gc protein + NSm domain V signal peptide
-
a Bunyamwera orthobunyavirus glycoprotein precursor-derived structural glycoprotein
-
-
?
sterol regulatory element-binding protein + H2O
?
-
SrbA is sequentially cleaved by Dsc complex-linked proteolysis and SppA
-
-
?
sterol regulatory element-binding protein + H2O
?
Aspergillus nidulans A773
-
SrbA is sequentially cleaved by Dsc complex-linked proteolysis and SppA
-
-
?
additional information
?
-
peptidase SppABS self-processes its own C-terminus. The processing occurs very quickly and is complete before the enzyme can be purified. No trans-processing is observed between wild-type and active site mutants
-
-
?
additional information
?
-
-
peptidase SppABS self-processes its own C-terminus. The processing occurs very quickly and is complete before the enzyme can be purified. No trans-processing is observed between wild-type and active site mutants
-
-
?
additional information
?
-
peptidase SppABS self-processes its own C-terminus. The processing occurs very quickly and is complete before the enzyme can be purified. No trans-processing is observed between wild-type and active site mutants
-
-
?
additional information
?
-
-
SPP interacts specifically and tightly with a large range of newly synthesized membrane proteins, including signal peptides, preproteins and misfolded membrane proteins, but not with all co-expressed type II membrane proteins. Preproteins and misfolded membrane proteins interact with SPP, and are not substrates for SPP-mediated intramembrane proteolysis. Proteins interacting with SPP are found in distinct complexes of different sizes. A signal peptide is mainly trapped in a 200 kDa SPP complex, whereas a preprotein is predominantly found in a 600 kDa SPP complex. A misfolded membrane protein is detected in 200, 400 and 600 kDa SPP complexes. SPP not only processes signal peptides, but also collects preproteins and misfoldedmembrane proteins that are destined for disposal
-
-
?
additional information
?
-
-
pro-prolactin interacts with signal peptide peptidase, without being processed
-
-
?
additional information
?
-
-
cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP
-
-
-
additional information
?
-
-
cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP
-
-
?
additional information
?
-
-
for heme oxygenase-1, HO-1, the endoplasmic reticlum anchor of HO-1 is necessary for SPP-binding, and the membrane anchor, the PEST-domain and the nuclear shuttle sequence of HO-1 are necessary for full cleavage and subsequent translocation under hypoxic conditions. Under hypoxic conditions, SPP mediates intramembrane cleavage of HO-1, but not HO-2. Translocation mechanism of HO-1, overview. The HO-1 anchor mutant (SF275/276AL) is partially resistant to SPP-mediated cleavage. Sequence comparison of substrates heme oxygenases 1 and 2
-
-
-
additional information
?
-
-
for heme oxygenase-1, HO-1, the endoplasmic reticlum anchor of HO-1 is necessary for SPP-binding, and the membrane anchor, the PEST-domain and the nuclear shuttle sequence of HO-1 are necessary for full cleavage and subsequent translocation under hypoxic conditions. Under hypoxic conditions, SPP mediates intramembrane cleavage of HO-1, but not HO-2. Translocation mechanism of HO-1, overview. The HO-1 anchor mutant (SF275/276AL) is partially resistant to SPP-mediated cleavage. Sequence comparison of substrates heme oxygenases 1 and 2
-
-
?
additional information
?
-
proteolytic activity of SPPL2c has not been demonstrated and similarly the physiological functions of SPPL2c
-
-
-
additional information
?
-
proteolytic activity of SPPL2c has not been demonstrated and similarly the physiological functions of SPPL2c
-
-
?
additional information
?
-
-
signal peptide peptidase (SPP) requires both conformational flexibility and site-specific interactions to proteolyze its substrate. THe substrates' cleavage site motifs facilitates SPP-catalyzed cleavage of TA proteins. Mass spectrometry-based mapping of SPP-cleavage sites
-
-
-
additional information
?
-
-
signal peptide peptidase (SPP) requires both conformational flexibility and site-specific interactions to proteolyze its substrate. THe substrates' cleavage site motifs facilitates SPP-catalyzed cleavage of TA proteins. Mass spectrometry-based mapping of SPP-cleavage sites
-
-
?
additional information
?
-
-
cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP
-
-
-
additional information
?
-
-
cleavage occurs following ectodomain shedding by signal peptidase (SP) for hSPP
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
-
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
?
additional information
?
-
SPP and SPPL cleavage mechanisms, overview. All SPPL3 substrates identified are type II transmembrane proteins. Mechanistically, SPPL3-mediated intramembrane cleavage induces the secretion of the substrate's ectodomain, thereby reducing the intracellular levels of active glycosyltransferases
-
-
?
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
-
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
?
additional information
?
-
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPP and SPPL cleavage mechanisms, overview
-
-
?
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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
Bri2 + H2O
?
release of an intracellular peptide
-
-
?
protein Gc precursor + H2O
mature Gc protein + NSm domain V signal peptide
-
a Bunyamwera orthobunyavirus glycoprotein precursor-derived structural glycoprotein
-
-
?
protein NSm precursor + H2O
mature NSm protein + NSm domain I signal peptide
-
a Bunyamwera orthobunyavirus glycoprotein precursor-derived nonstructural protein
-
-
?
additional information
?
-
-
SPP interacts specifically and tightly with a large range of newly synthesized membrane proteins, including signal peptides, preproteins and misfolded membrane proteins, but not with all co-expressed type II membrane proteins. Preproteins and misfolded membrane proteins interact with SPP, and are not substrates for SPP-mediated intramembrane proteolysis. Proteins interacting with SPP are found in distinct complexes of different sizes. A signal peptide is mainly trapped in a 200 kDa SPP complex, whereas a preprotein is predominantly found in a 600 kDa SPP complex. A misfolded membrane protein is detected in 200, 400 and 600 kDa SPP complexes. SPP not only processes signal peptides, but also collects preproteins and misfoldedmembrane proteins that are destined for disposal
-
-
?
CD74 + H2O
?
-
although SPPL2b can cleave CD74 when overexpressed, it does not appear contribute to CD74 NH2-terminal fragment turnover
-
-
?
CD74 + H2O
?
-
SPPL2a cleaves CD74 and contributes to CD74 NH2-terminal fragment turnover
-
-
?
CD74 NTF + H2O
?
release of intracellular peptide
-
-
?
sterol regulatory element-binding protein + H2O
?
-
SrbA is sequentially cleaved by Dsc complex-linked proteolysis and SppA
-
-
?
sterol regulatory element-binding protein + H2O
?
Aspergillus nidulans A773
-
SrbA is sequentially cleaved by Dsc complex-linked proteolysis and SppA
-
-
?
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-[2-(trifluoromethyl)phenyl]butanediamide
-
-
(2R)-2-methyl-N4-(2-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
(2R)-2-methyl-N4-(2-methylpyridin-3-yl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-2-methyl-N4-(3-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-2-methyl-N4-(4-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N1-[(10S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methylbutanediamide
-
-
(2R)-N4-(3,5-difluorophenyl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-N1-[(10S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-2-methylbutanediamide
-
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-1'H,3'H,5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
(2S)-2-cyclopropyl-N1-[(10S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
-
(S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
LY-411575
N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide
N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide
NH3-SPRMMYLYAK-COOH
peptide synthesized corresponding to the sequence of the modeled C-terminal peptide bound in the SppA substrate-binding groove. Competitive inhibition
[(2R,4R,5S)-2-benzyl-5-(t-butyloxycarbonylamino)-4-hydroxy-6-phenylhexanoyl]-L-leucyl-L-phenylalanine amide
(2R)-2-methyl-N4-(2-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
reversible, inhibits CD74/p8 processing in vivo and spares gamma-secretase activity
-
(2R)-2-methyl-N4-(2-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-2-methyl-N4-(2-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-N1-[(10S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-2-methylbutanediamide
-
-
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-N1-[(10S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-2-methylbutanediamide
-
-
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
-
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
-
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
-
-
(S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
-
i.e. Compound E
(S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
-
i.e. Compound E, below 50% inhibition
1,3-di-(N-carboxybenzoyl-L-leucyl-L-leucyl) amino acetone
signal peptide peptidase specific inhibitor
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
-
i.e. (Z-LL)2 ketone
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
(Z-LL)2-ketone
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
-
i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
-
i.e. (Z-LL)2 ketone
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
(Z-LL)2-ketone; (Z-LL)2-ketone; (Z-LL)2-ketone
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
(Z-LL)2-ketone
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
-
i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
-
i.e. (Z-LL)2 ketone, causes over 75% inhibition of FBA cleavage at 0.01 mM
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
(Z-LL)2-ketone
N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide
-
i.e. DBZ
N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide
DBZ; DBZ
[(2R,4R,5S)-2-benzyl-5-(t-butyloxycarbonylamino)-4-hydroxy-6-phenylhexanoyl]-L-leucyl-L-phenylalanine amide
aspartic protease inhibitor that targets signal peptide peptidase or presenilin
[(2R,4R,5S)-2-benzyl-5-(t-butyloxycarbonylamino)-4-hydroxy-6-phenylhexanoyl]-L-leucyl-L-phenylalanine amide
-
additional information
-
increasing the rigidity of the transmembrane helices prevents SPP-catalyzed cleavage
-
additional information
development and synthesis of potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitors displaying pronounced immunomodulatory effects in vivo. Selectivity of inhibitors for SPP compared to gamma-secretase, overview
-
additional information
SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] ((Z-LL)2-ketone), L-685,458, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752; SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), weak inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] ((Z-LL)2-ketone), L-685,458, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752; SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), weak inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] ((Z-LL)2-ketone), L-685,458, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752; SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), weak inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by 2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide] ((Z-LL)2-ketone), L-685,458, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E); SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752; SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors is demonstrated. No inhibition by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), weak inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
development and synthesis of potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitor displaying pronounced immunomodulatory effects in vivo. Selectivity of inhibitors for SPP compared to gamma-secretase, overview
-
additional information
-
development and synthesis of potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitor displaying pronounced immunomodulatory effects in vivo. Selectivity of inhibitors for SPP compared to gamma-secretase, overview
-
additional information
-
no inhibition by N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ); no inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
inhibition of Plasmodium SPP (PlSPP) can be of clinical relevance for fighting malaria infections. SPP inhibitors for Plasmodium block SPP. SPP-mediated proteolysis might cause endoplasmic reticulum stress leading to an altered Plasmodium life cycle and growth inhibition. The developmental stage of Plasmodium is affected by PlSPP inhibition
-
additional information
-
no inhibition by (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide (Compound E) and N-[(1S)-2-[[(7S)-6,7-Dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide (DBZ)
-
additional information
development and synthesis of potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitor displaying pronounced immunomodulatory effects in vivo. Seletivity of inhibitors for SPP compared to gamma-secretase, overview
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Alzheimer Disease
Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins.
Alzheimer Disease
Signal peptide peptidase dependent cleavage of type II transmembrane substrates releases intracellular and extracellular signals.
Breast Neoplasms
Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function.
Carcinoma, Hepatocellular
A small molecule inhibitor of signal Peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity.
Classical Swine Fever
Core protein of pestiviruses is processed at the C terminus by signal peptide peptidase.
Dehydration
Physiological and molecular responses for long term salinity stress in common fig (Ficus carica L.).
Dementia
The ?-Helical Content of the Transmembrane Domain of the British Dementia Protein-2 (Bri2) Determines Its Processing by Signal Peptide Peptidase-like 2b (SPPL2b).
Glioblastoma
Signal Peptide Peptidase, Encoded by HM13, Contributes to Tumor Progression by Affecting EGFRvIII Secretion Profiles in Glioblastoma.
Hepatitis C
Characterization of SPP inhibitors suppressing propagation of HCV and protozoa.
Hepatitis C
Characterization of the cleavage of signal peptide at the C-terminus of hepatitis C virus core protein by signal peptide peptidase.
Hepatitis C
Core protein cleavage by signal peptide peptidase is required for hepatitis C virus-like particle assembly.
Hepatitis C
Efficient cleavage by signal peptide peptidase requires residues within the signal peptide between the core and E1 proteins of hepatitis C virus strain J1.
Hepatitis C
Hepatitis C virus core protein: carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase.
Hepatitis C
Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.
Hepatitis C
Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation.
Hepatitis C
Maturation of hepatitis C virus core protein by signal peptide peptidase is required for virus production.
Hepatitis C
Membrane binding properties and terminal residues of the mature hepatitis C virus capsid protein in insect cells.
Hepatitis C
Sequential processing of hepatitis C virus core protein by host cell signal peptidase and signal peptide peptidase: a reassessment.
Hepatitis C
Signal peptide peptidase dependent cleavage of type II transmembrane substrates releases intracellular and extracellular signals.
Hepatitis C
Signal peptide peptidase promotes the formation of hepatitis C virus non-enveloped particles and is captured on the viral membrane during assembly.
Hepatitis C
Structural analysis of hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase.
Hepatitis C
The potential of signal peptide peptidase as a therapeutic target for hepatitis C.
Herpes Simplex
Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo.
Infections
HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.
Infections
Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis.
Infections
Signal Peptide Peptidase Cleavage of GB Virus B Core Protein Is Required for Productive Infection in Vivo.
Infections
Signal peptide peptidase dependent cleavage of type II transmembrane substrates releases intracellular and extracellular signals.
Malaria
A small molecule inhibitor of signal Peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity.
Malaria
HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.
Malaria
Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase.
Malaria
Malaria Parasite Signal Peptide Peptidase is an ER-Resident Protease Required for Growth but not for Invasion.
Malaria
Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis.
Malaria
Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria.
Neoplasms
A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b.
Neoplasms
Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation.
Neoplasms
Novel biomarkers of mercury-induced autoimmune dysfunction: a cross-sectional study in Amazonian Brazil.
Neoplasms
Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing.
Neoplasms
Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation.
Neoplasms
Signal Peptide Peptidase, Encoded by HM13, Contributes to Tumor Progression by Affecting EGFRvIII Secretion Profiles in Glioblastoma.
Neoplasms
SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production.
Parkinson Disease
STK39, But Not BST1, HLA-DQB1, and SPPL2B Polymorphism, Is Associated With Han-Chinese Parkinson's Disease in Taiwan.
Virus Diseases
Signal Peptide Peptidase Cleavage of GB Virus B Core Protein Is Required for Productive Infection in Vivo.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00285
(2R)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-[2-(trifluoromethyl)phenyl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000035
(2R)-2-methyl-N4-(2-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.00102
(2R)-2-methyl-N4-(2-methylpyridin-3-yl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.00007
(2R)-2-methyl-N4-(3-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.00139
(2R)-2-methyl-N4-(4-methylphenyl)-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.00087
(2R)-N1-[(10S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methylbutanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000005
(2R)-N4-(3,5-difluorophenyl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000044
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-2-methyl-N1-[(10S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000076
(2R)-N4-(5-fluoro-2-methylpyridin-3-yl)-N1-[(10S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-2-methylbutanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000077
(2S)-2-cyclopropyl-N1-[(10'S)-5',11'-dioxo-10',11'-dihydro-5'H-spiro[cyclopropane-1,2'-pyrazolo[1,2-b][2,3]benzodiazepin]-10'-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.000225
(2S)-2-cyclopropyl-N1-[(10S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-pyrazolo[1,2-b][2,3]benzodiazepin-10-yl]-N4-(5-fluoro-2-methylpyridin-3-yl)butanediamide
Homo sapiens
pH 7.4, 37°C, liver microsomes
-
0.00146
(S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
Homo sapiens
-
pH and temperature not specified in the publication
0.000177 - 0.006
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
0.000948
N-[(1S)-2-[[(7S)-6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]amino]-1-methyl-2-oxoethyl]-3,5-difluorobenzeneacetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.000177
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Mus musculus
-
pH and temperature not specified in the publication
0.000472
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Plasmodium sp.
-
pH and temperature not specified in the publication
0.000519
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Homo sapiens
-
pH and temperature not specified in the publication
0.00214
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Mus musculus
-
pH and temperature not specified in the publication
0.006
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Homo sapiens
pH 7.4, 37°C
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high SPPL2b expression rate
brenda
additional information
additional information
plant infection studies using the Zea mays cultivar Early Golden Bantam
brenda
additional information
-
plant infection studies using the Zea mays cultivar Early Golden Bantam
brenda
additional information
-
plant infection studies using the Zea mays cultivar Early Golden Bantam
-
brenda
additional information
-
plant infection studies using the Zea mays cultivar Early Golden Bantam
-
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
overexpressed SPPL2c localises to the endoplasmic reticulum
brenda
overexpressed SPP localises to the endoplasmic reticulum
brenda
-
SppA interacts with the sterol regulatory element-binding protein SrbA in the endoplasmic reticulum, where SppA localizes in normoxia and hypoxia
brenda
Aspergillus nidulans A773
-
SppA interacts with the sterol regulatory element-binding protein SrbA in the endoplasmic reticulum, where SppA localizes in normoxia and hypoxia
-
brenda
Spp1 displays the characteristic SPP domain structure with 9 predicted trans membrane (TM) domains
brenda
-
Spp1 displays the characteristic SPP domain structure with 9 predicted trans membrane (TM) domains
-
brenda
-
Spp1 displays the characteristic SPP domain structure with 9 predicted trans membrane (TM) domains
-
brenda
n-dodecyl-beta-maltoside-solubilized membrane fraction
brenda
-
signal peptide peptidase (SPP) is a membrane-bound enzyme
brenda
-
signal peptide peptidase (SPP) is a membrane-bound enzyme
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
-
similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
evolution
-
similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
evolution
-
similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
malfunction
-
both null and dead activity mutants of sppA fail to grow in hypoxia, and the growth defect of DELTAsppA is complemented by nuclear SrbA-N381 expression. The loss of SppA or Dsc orthologs leads to the mislocalization of sterol regulatory element-binding protein SrbA within the cell. Expression of the truncated SrbA-N414 covering the SrbA sequence prior to the second transmembrane region rescues the growth of DELTAdscA but not of DELTAsppA in hypoxia
malfunction
-
depletion of SPPL2a leads to accumulation of an NH2-terminal fragment (NTF) of CD74 which impairs B cell development and survival
malfunction
-
dramatic decreases in the concentrations of both signal peptide peptidases SppA and TepA (45 and 49%, respectively) in a sppA deficient strain, while the extracellular protein yields of nattokinase and alpha-amylase are increased by 30% and 67% respectively in a strain overexpressing SppA. In addition, biomass, specific enzyme activities and the relative gene transcriptional levels are also enhanced due to the overexpression of sppA, while altering the expression levels of tepA has no effect on the concentrations of the secreted target proteins
malfunction
-
increasing the rigidity of the transmembrane helices prevents SPP-catalyzed cleavage. The C-terminal di-glycine XBP1u mutants show local TM helix destabilization
malfunction
-
inhibition of SPP and SKI-1 activity does not interfere with SFTSV Gn + Gc-driven host cell entry but blocks entry driven by the EBOV glycoprotein, the SPP inhibitor blocks CatL and CatB activity, mechanism, overview. Inhibitors of signal peptide peptidase and subtilisin/kexin-isozyme 1 inhibit Ebola virus glycoprotein-driven cell entry by interfering with activity and cellular localization of endosomal cathepsins. Infectivity of VSV-G bearing pseudotypes is not markedly modulated by SPP inhibitor. The SPP inhibitor does not modulate infectivity of SFTSV-Gn/Gc pseudotypes. The SPP inhibitor has only a modest effect on infectivity of LASV-GPC-bearing pseudotypes. While infectivity of EBOV-GP-bearing pseudotypes is markedly reduced by SPP inhibitor
malfunction
loss of virulence is connected to the catalytic activity of Spp1 to interfere with plant defense responses. Endoplasmic reticulum stress resistance of UPR core gene deletion mutants. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
malfunction
SPP knockout mice show embryonic lethality. But at least in immortalised, continuously proliferating cell lines, a loss of SPP and any potentially resulting proteostatic dysbalance can be compensated
malfunction
SPPL2b knockout mice show no altered phenotype and are viable. In vivo depletion of SPPL2b does not influence the levels of the CD74 NTF fragment. SPPL2b-deficient mice display no alterations in B cell development or function. Combined ablation of SPPL2a/b does not aggravate the biochemical and physiological consequences observed in the SPPL2a single-deficient mice, arguing for at least partially non-redundant functions of both GxGD proteases in this cell type which is most likely caused by their differential subcellular distributions
malfunction
SPPL3 knockout mice show perinatal lethality (C57/Bl6 J mice), growth retardation and reduction of NK cells (C57BL/6-129S5 mice), male sterility, and impaired NK cell maturation and function (Vav1-iCre and NKp46-iCre mice). SPPL3 overexpression leads to hypoglycosylation of cellular proteins in the secretory pathway and, vice versa, a depletion of SPPL3 to enhanced glycan synthesis. Based on the enzyme's role as sheddase of glycosyltransferases and glycan-modifying enzymes, glycoproteins in tissues of SPPL3-/- mice are hyperglycosylated. SPPL3 deficiency in natural killer (NK) cells leads to a significant reduction of peripheral NK cells in spleen and liver, which is caused by a reduced proliferation of CD27+CD11b- precursors in the bone marrow and impaired survival of CD27+CD11b+ and CD27-CD11b+ NK cells in both bone marrow and periphery. The remaining cells exhibit altered surface expression of several NK cell receptors and reduced cytotoxicity. These changes are not rescued in SPPL3-/D271A NK cells expressing the inactive SPPL3-D271A mutant which demonstrates a requirement of the SPPL3 proteolytic activity in this cell type. SPPL3 knockdown in Jurkat T-cells diminishes the cytosolic Ca2+ entry and activation of the transcription factor NFAT upon activation of the T cell receptor (TCR). The differentiation of T-cells is not negatively affected by SPPL3 deficiency which is demonstrated by normal numbers of CD4+ and CD8+ T-cells in spleens of Vav1-iCre SPPL3 knockout mice
malfunction
SPPLa knockout mice are viable and show a phenotype with arrest of splenic B cell maturation, reduction of dendritic cells, and tooth enamel mineralisation defects. SPPL2a-deficient mice are characterised by a global depletion of B lymphocytes. Also the remaining B cells exhibit a major functional deficit, antibody production and humoral immune responses are significantly impaired. SPPL2a-deficiency is linked with the disrupted proteolysis of CD74, the invariant chain of the MHCII complex (MHCII). Combined ablation of SPPL2a/b does not aggravate the biochemical and physiological consequences observed in the SPPL2a single-deficient mice, arguing for at least partially non-redundant functions of both GxGD proteases in this cell type which is most likely caused by their differential subcellular distributions
malfunction
-
stable depletion of SPP expression in lung and breast cancer cell lines significantly reduces cell growth and migration/invasion abilities. The level of FKBP8, an endogenous inhibitor of mTOR, is significantly increased following SPP depletion, and the levels of phosphorylation in mTOR and its downstream effectors, S6K and 4E-BP1, are significantly lower in SPP-depleted cells. The reduced mTOR signaling and decreases of growth and migration/invasion abilities induced by SPP depletion in cancer cells can be reversed by FKBP8 downregulation. Downregulation of SPP suppresses cell growth, migration, and invasion, cell phenotypes, overview
malfunction
-
loss of virulence is connected to the catalytic activity of Spp1 to interfere with plant defense responses. Endoplasmic reticulum stress resistance of UPR core gene deletion mutants. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
-
malfunction
Aspergillus nidulans A773
-
both null and dead activity mutants of sppA fail to grow in hypoxia, and the growth defect of DELTAsppA is complemented by nuclear SrbA-N381 expression. The loss of SppA or Dsc orthologs leads to the mislocalization of sterol regulatory element-binding protein SrbA within the cell. Expression of the truncated SrbA-N414 covering the SrbA sequence prior to the second transmembrane region rescues the growth of DELTAdscA but not of DELTAsppA in hypoxia
-
malfunction
-
dramatic decreases in the concentrations of both signal peptide peptidases SppA and TepA (45 and 49%, respectively) in a sppA deficient strain, while the extracellular protein yields of nattokinase and alpha-amylase are increased by 30% and 67% respectively in a strain overexpressing SppA. In addition, biomass, specific enzyme activities and the relative gene transcriptional levels are also enhanced due to the overexpression of sppA, while altering the expression levels of tepA has no effect on the concentrations of the secreted target proteins
-
malfunction
-
loss of virulence is connected to the catalytic activity of Spp1 to interfere with plant defense responses. Endoplasmic reticulum stress resistance of UPR core gene deletion mutants. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
-
metabolism
gene spp1, encoding the signal peptide peptidase, belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant. The virulence specific function of Spp1 does not involve pathways previously known to be associated with Spp1-like proteins or plant defense suppression
metabolism
-
gene spp1, encoding the signal peptide peptidase, belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant. The virulence specific function of Spp1 does not involve pathways previously known to be associated with Spp1-like proteins or plant defense suppression
-
metabolism
-
gene spp1, encoding the signal peptide peptidase, belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant. The virulence specific function of Spp1 does not involve pathways previously known to be associated with Spp1-like proteins or plant defense suppression
-
physiological function
-
signal peptide peptidase forms a complex with the ER-associated degradation factor Derlin1 and the E3 ubiquitin ligase TRC8 to cleave the unfolded protein response regulator XBP1u. Cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an signal peptide peptidase substrate through specific sequence features. Additionally, Derlin1 acts in the complex as a substrate receptor by recognizing the luminal tail of XBP1u
physiological function
-
signal peptide peptidase SPP catalyzes the intramembrane cleavage of heme oxygenase HO-1. Coexpression of HO-1 with wild-type SPP promotes the nuclear localization of HO-1 in cells. Two adjacent intramembrane cleavage sites are located after S275 and F276 within the trans membrane segment. Mutations of S275F276 to A275L276 significantly hinder SPP-mediated cleavage and nuclear localization. Nuclear heme oxygenase-1 is detected in A549 and DU145 cancer cell lines expressing high levels of endogenous HO-1 and SPP. SPP knockdown or inhibition significantly reduces nuclear HO-1 localization in A549 and DU145 cells. The positive nuclear HO-1 stain is also evident in lung cancer tissues expressing high levels of HO-1 and SPP. Overexpression of a truncated HO-1 lacking the trans membrane segment in HeLa and H1299 cells promotes cell proliferation and migration/invasion
physiological function
-
type-I signal peptide peptidase SPP1 is essential for parasite survival both in vitro and in vivo. Expression of catalytically inactive SPP1 is unable to rescue cells from the SPP1 depleted phenotype
physiological function
-
Bunyamwera orthobunyavirus glycoprotein precursor is proteolytically processed by cellular signal peptidase and signal peptide peptidase to yield two viral structural glycoproteins, Gn and Gc, and a nonstructural protein, NSm. Both NSm and Gc proteins are cleaved at their own internal signal peptides (SPs), in which NSm domain I functions as SPNSm and NSm domain V as SPGc.Moreover, the domain I is further processed by the host intramembrane-cleaving protease, signal peptide peptidase, and is required for cell fusion activities. Meanwhile, the NSm domain V (SPGc) remains integral to NSm, rendering the NSm topology as a two-membrane-spanning integral membrane protein. The NSm domain V functions as an internal noncleavable SPGcCleavage sites and cleavage mechanism, overview
physiological function
involvement of SPPL2c in acrosome formation during spermatogenesis
physiological function
-
signal peptide peptidase (SPP) can catalyze the intramembrane cleavage of heme oxygenase-1 (HO-1) that leads to translocation of HO-1 into the cytosol and nucleus, mechanism of isoenzyme-specific signal peptide peptidase-mediated translocation of heme oxygenase and its regulation by SPP, overview. The translocation is independent of the catalytic activity of HO-1, the inactive HO-1 mutant H25A is also translocated. HO-1 and the closely related heme oxygenase-2 (HO-2) isoenzyme bind to SPP under normoxic conditions. Under hypoxic conditions, SPP mediates intramembrane cleavage of HO-1, but not HO-2
physiological function
-
signal peptide peptidase (SPP) is an endoplasmic reticulum (ER)-resident aspartyl protease mediating intramembrane cleavage of type II transmembrane proteins, role of SPP in ER-associated protein degradation. SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome. SPP interacts and colocalizes with FKBP8 in the endoplasmic reticulum. SPP-mediated proteolysis facilitates FKBP8 protein degradation in the cytosol. SPP promotes tumor progression, at least in part, via facilitating the degradation of FKBP8 to enhance mTOR signaling
physiological function
-
signal peptide peptidase (SPP) is an intramembrane aspartyl protease that cleaves membrane associated signal peptides following their liberation from nascent proteins by signal peptidase. Signal peptide peptidase (SPP) is required for processing of the glycoprotein precursor, Gn/Gc, of Bunyamwera virus and for viral infectivity
physiological function
-
signal peptide peptidase (SPP) uses a serine/lysine catalytic dyad mechanism to cleave the remnant signal peptides in the cellular membrane and aids in protein secretion
physiological function
signal peptide peptidase activity connects the unfolded protein response (UPR) to plant defense suppression by Ustilago maydis. The corn smut fungus Ustilago maydis requires the unfolded protein response to maintain homeostasis of the endoplasmic reticulum during the biotrophic interaction with its host plant Zea mays. The signal peptide peptidase Spp1 is a key factor that is required for establishing a compatible biotrophic interaction between Ustilago maydis and its host plant maize. Spp1 is dispensable for endoplasmic reticulum stress resistance and vegetative growth but its catalytic activity is required to interfere with the plant defense, revealing a virulence specific function for signal peptide peptidases in a biotrophic fungal/plant interaction. The UPR-regulated signal peptide peptidase Spp1 is dispensable for vegetative growth or filament formation, but is of crucial importance to establish a compatible biotrophic interaction and cause disease
physiological function
signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease playing an important role in the development and function of antigen presenting cells such as B-lymphocytes and dendritic cells
physiological function
signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease playing an important role in the development and function of antigen presenting cells such as B-lymphocytes and dendritic cells
physiological function
signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease playing an important role in the development and function of antigen presenting cells such as B-lymphocytes and dendritic cells
physiological function
SPP cleaves and processes signal peptides and tail-anchored proteins/peptides from several proteins. Selected endoplasmic reticulum-localised tail-anchored (TA) proteins like heme oxygenase 1 (HO-1) are SPP substrates. In case of HO-1, nuclear translocation of the released intracellular peptide is observed, in cancer cells, this fragment enhances proliferation and migration. SPP forms complexes with components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway like the pseudoprotease Derlin-1 as well as the ubiquitin ligase TRC8. Mechanistically, SPP can modulate ERAD by cleaving the ERAD regulator X-box binding protein 1 (XBP1u), which can inhibit the unfolded protein response (UPR)-inducing functions of its spliced isoform XBP1s. But SPP may also actively participate in the ERAD process after associating with misfolded membrane proteins in large oligomeric complexes in the ER membrane. Mammalian SPP can regulate cellular nutrient uptake
physiological function
SPPL2a cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Membrane-bound CD74 NTF depends on SPPL2a for its removal from the membrane. Upon SPPL2a-mediated proteolysis of CD74, a CD74 ICD is released into the cytosol which is capable of entering the nucleus, regulatory functions of this cleavage fragment, in particular in B-cells
physiological function
SPPL2b cleaves signal peptides and tail-anchored proteins/peptides from proteins. SPPL2b utilises multiple cleavages within the transmembrane domains (TDMs) of their substrates to release the products from the membrane. Starting from the C-terminal end of the substrates TMD, the protease releases the first cleavage product with an initial cut and proceeds in a consecutive manner towards the N-terminal end of the substrates TMD until the remaining hydrophobic sequence is short enough to detach from the membrane releasing the second cleavage product. SPPL2b-dependent processing of Bri2, a modulator of amyloid neurodegenerative diseases. SPPL2b-dependent proteolysis liberates a small Bri2 intracellular peptide (ICD) to the cytosol, that may translocate to the nucleus and act as transcriptional regulator. Bri2 upregulates expression of the Abeta-degrading protease insulin degrading enzyme (IDE)
physiological function
SPPL3 is able to cleave a large set of Golgi-resident glycosyltransferases and glycan-modifying enzymes which are involved in protein N- and O-glycosylation as well as glycosaminoglycan biosynthesis. SPPL3 has emerged as a major regulator of cellular protein glycosylation. Role of SPPL3 in natural killer cell maturation and function. SPPL3 facilitates the interaction of the endoplasmic reticulum protein STIM1 and the calcium channel Orai1 which is a key element of Store-operated calcium entry (SOCE) critically involved in T-cell activation but also signal transduction in other immune and non-immune cells
physiological function
-
the signal peptide peptidase (SPP) SppA, an aspartyl protease involved in regulated intramembrane proteolysis (RIP), is essential for hypoxia adaptation in Aspergillus nidulans. Importance of SppA and the Dsc complex for nuclear localization of sterol regulatory element-binding protein (SREBP) SrbA in hypoxia. Sequential cleavage of SrbA by Dsc-linked proteolysis followed by SppA, proposing another model of RIP for sterol regulatory element-binding protein (SREBP) srbA cleavage in fungal hypoxia adaptation
physiological function
-
signal peptide peptidase activity connects the unfolded protein response (UPR) to plant defense suppression by Ustilago maydis. The corn smut fungus Ustilago maydis requires the unfolded protein response to maintain homeostasis of the endoplasmic reticulum during the biotrophic interaction with its host plant Zea mays. The signal peptide peptidase Spp1 is a key factor that is required for establishing a compatible biotrophic interaction between Ustilago maydis and its host plant maize. Spp1 is dispensable for endoplasmic reticulum stress resistance and vegetative growth but its catalytic activity is required to interfere with the plant defense, revealing a virulence specific function for signal peptide peptidases in a biotrophic fungal/plant interaction. The UPR-regulated signal peptide peptidase Spp1 is dispensable for vegetative growth or filament formation, but is of crucial importance to establish a compatible biotrophic interaction and cause disease
-
physiological function
Aspergillus nidulans A773
-
the signal peptide peptidase (SPP) SppA, an aspartyl protease involved in regulated intramembrane proteolysis (RIP), is essential for hypoxia adaptation in Aspergillus nidulans. Importance of SppA and the Dsc complex for nuclear localization of sterol regulatory element-binding protein (SREBP) SrbA in hypoxia. Sequential cleavage of SrbA by Dsc-linked proteolysis followed by SppA, proposing another model of RIP for sterol regulatory element-binding protein (SREBP) srbA cleavage in fungal hypoxia adaptation
-
physiological function
-
signal peptide peptidase (SPP) uses a serine/lysine catalytic dyad mechanism to cleave the remnant signal peptides in the cellular membrane and aids in protein secretion
-
physiological function
-
signal peptide peptidase activity connects the unfolded protein response (UPR) to plant defense suppression by Ustilago maydis. The corn smut fungus Ustilago maydis requires the unfolded protein response to maintain homeostasis of the endoplasmic reticulum during the biotrophic interaction with its host plant Zea mays. The signal peptide peptidase Spp1 is a key factor that is required for establishing a compatible biotrophic interaction between Ustilago maydis and its host plant maize. Spp1 is dispensable for endoplasmic reticulum stress resistance and vegetative growth but its catalytic activity is required to interfere with the plant defense, revealing a virulence specific function for signal peptide peptidases in a biotrophic fungal/plant interaction. The UPR-regulated signal peptide peptidase Spp1 is dispensable for vegetative growth or filament formation, but is of crucial importance to establish a compatible biotrophic interaction and cause disease
-
additional information
endogenous SPP expression is not affected by human SPPL2c overexpression
additional information
-
signal peptide peptidase (SPP) requires both conformational flexibility and site-specific interactions to proteolyze its substrate. SPP cleavage is governed by transmembrane (TM) helix dynamics and site-specific features. Introducing transmembrane leucine and glycine residues in SPP changes helix dynamics. SPP-catalyzed intramembrane proteolysis of TM helices is not only determined by their conformational flexibility, but also by side-chain interactions near the scissile peptide bond with the enzyme's active site
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). A0A0D1E4M7_USTMA
Ustilago maydis (strain 521 / FGSC 9021)
416
0
46022
TrEMBL
-
SPP2C_HUMAN
684
0
74503
Swiss-Prot
other Location (Reliability: 4)
SPP2A_MOUSE
523
0
58129
Swiss-Prot
Secretory Pathway (Reliability: 1)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
26624
x * 26624, electrospray ionization mass spectrometry of protease resistant fragment Leu51-Gly295
28000
8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
35000
36000
8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
65000
65000
x * 65000, SDS-PAGE, fusion construct with green fluorescent protein
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
octamer
additional information
?
x * 65000, SDS-PAGE, fusion construct with green fluorescent protein
?
x * 26624, electrospray ionization mass spectrometry of protease resistant fragment Leu51-Gly295
?
-
x * 26624, electrospray ionization mass spectrometry of protease resistant fragment Leu51-Gly295
-
?
-
x * 37000, recombinant FLAG-tagged enzyme, SDS-PAGE, x * 52000, about, sequence calculation
octamer
8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
octamer
-
8 * 36000, SDS-PAGE. 8 * 28000, SDS-PAGE after limited digestion using thermolysin
-
additional information
-
signal peptides have a common three-domain structure comprised by a short positive-charged n-region, a hydrophobic h-region of 7-15 residues, and a polar c-region including the site for signal peptidase cleavage
additional information
SPP/SPPL proteases either act as mono- or homodimers
additional information
-
the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer
additional information
SPP/SPPL proteases either act as mono- or homodimers
additional information
SPP/SPPL proteases either act as mono- or homodimers
additional information
SPP/SPPL proteases either act as mono- or homodimers
additional information
SPP/SPPL proteases either act as mono- or homodimers
additional information
-
the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer
additional information
-
the monomeric form is the dominant species observed for the recombinant enzyme, with lesser amounts of dimer and trimer. The enzyme has multiple intracellular domains (ICDs)
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
2.4-A resolution structure of Bacillus subtilis SppA catalytic domain reveals eight SppA molecules in the asymmetric unit, forming a dome-shaped octameric complex. Residue Ser147 may serve as the nucleophile and Lys199 may serve as the general base. The SppA S1 substrate specificity pocket is deep, narrow and hydrophobic, but with a polar bottom. The S3 pocket, which is constructed from two neighboring proteins, is shallower, wider and more polar than the S1 pocket
crystal structure of a proteolytically stable fragment of mutant K199A, residues Leu51-Gly295, that has its C-terminal peptide bound in each of the eight active sites, creating a perfect circle of peptides. Substrate specificity pockets accommodate C-terminal residues Tyr331, Met329, and Tyr333, respectively. The C-terminus binds within the substrate-binding grooves in an antiparallel beta-sheet fashion
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D337A
K199A
K199A
D265A
-
inactive. Signal peptides are trapped by the catalytically inactive SPP mutant. Preproteins and misfolded membrane proteins interact with both wild-type SPP and the mutant
additional information
additional information
-
generation of a knockout enzyme null mutant DELTAsppA
additional information
Aspergillus nidulans A773
-
generation of a knockout enzyme null mutant DELTAsppA
-
additional information
-
improvement of protein secretion via overexpression of the SppA signal peptide peptidase in Bacillus licheniformis. Enzyme knockout of gene sppA, encoding the signal peptide peptidase, individually in Bacillus licheniformis strain BL10. Overexpression of sppA could not only improve the protein secretion level, but also enhance the biomass yield
additional information
-
improvement of protein secretion via overexpression of the SppA signal peptide peptidase in Bacillus licheniformis. Enzyme knockout of gene sppA, encoding the signal peptide peptidase, individually in Bacillus licheniformis strain BL10. Overexpression of sppA could not only improve the protein secretion level, but also enhance the biomass yield
-
additional information
construction of C-terminal deletion mutants DELTA329-335, DELTA307-335 and DELTA295-335. The C-terminus is not essential for oligomerization of the enzyme
additional information
-
construction of C-terminal deletion mutants DELTA329-335, DELTA307-335 and DELTA295-335. The C-terminus is not essential for oligomerization of the enzyme
additional information
-
construction of C-terminal deletion mutants DELTA329-335, DELTA307-335 and DELTA295-335. The C-terminus is not essential for oligomerization of the enzyme
-
additional information
endogenous SPP expression is not affected by human SPPL2c overexpression
additional information
-
lung (H-1299) and breast (MCF-7 and MDA-MB-231) cancer cell lines with stable SPP knockdown mediated by two different specific shRNAs targeting SPP are established. Stable depletion of SPP expression in lung and breast cancer cell lines significantly reduces cell growth and migration/invasion abilities
additional information
generation of constitutive SPP knockout mice. The constitutive knockout of this protease leads to embryonic lethality after day 13.5, however without apparent histological abnormalities in the SPP-/- mouse embryos. At least in immortalised, continuously proliferating cell lines a loss of SPP and any potentially resulting proteostatic dysbalance can be compensated
additional information
generation of constitutive SPP knockout mice. The constitutive knockout of this protease leads to embryonic lethality after day 13.5, however without apparent histological abnormalities in the SPP-/- mouse embryos. At least in immortalised, continuously proliferating cell lines a loss of SPP and any potentially resulting proteostatic dysbalance can be compensated
additional information
generation of constitutive SPP knockout mice. The constitutive knockout of this protease leads to embryonic lethality after day 13.5, however without apparent histological abnormalities in the SPP-/- mouse embryos. At least in immortalised, continuously proliferating cell lines a loss of SPP and any potentially resulting proteostatic dysbalance can be compensated
additional information
generation of constitutive SPP knockout mice. The constitutive knockout of this protease leads to embryonic lethality after day 13.5, however without apparent histological abnormalities in the SPP-/- mouse embryos. At least in immortalised, continuously proliferating cell lines a loss of SPP and any potentially resulting proteostatic dysbalance can be compensated
additional information
generation of constitutive SPPL2a knockout mice. Constitutive SPPL2a knockout mice are viable. Three different strains of SPPL2a-deficient mice are generated by gene targeting or derived from N-ethyl-N-nitrosourea (ENU) mutagenesis screens. All three models exhibit a characteristic B cell differentiation defect that manifests during the so-called transitional (T) stages of splenic B cell maturation which these cells have to pass through prior to becoming mature, antigen-reactive B cells. Whereas the T1 population is largely preserved in SPPL2a-/- mice, T2 B cells as well as subsequent stages like the mature B cells are significantly depleted. In addition to this maturation block of the follicular B cells also innate-like B cell populations like the marginal zone and B1 B cells are significantly reduced in SPPL2a-deficient mice so that these mice are characterised by a global depletion of B lymphocytes. Also the remaining B cells exhibit a major functional deficit, antibody production and humoral immune responses are significantly impaired. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2a knockout mice. Constitutive SPPL2a knockout mice are viable. Three different strains of SPPL2a-deficient mice are generated by gene targeting or derived from N-ethyl-N-nitrosourea (ENU) mutagenesis screens. All three models exhibit a characteristic B cell differentiation defect that manifests during the so-called transitional (T) stages of splenic B cell maturation which these cells have to pass through prior to becoming mature, antigen-reactive B cells. Whereas the T1 population is largely preserved in SPPL2a-/- mice, T2 B cells as well as subsequent stages like the mature B cells are significantly depleted. In addition to this maturation block of the follicular B cells also innate-like B cell populations like the marginal zone and B1 B cells are significantly reduced in SPPL2a-deficient mice so that these mice are characterised by a global depletion of B lymphocytes. Also the remaining B cells exhibit a major functional deficit, antibody production and humoral immune responses are significantly impaired. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2a knockout mice. Constitutive SPPL2a knockout mice are viable. Three different strains of SPPL2a-deficient mice are generated by gene targeting or derived from N-ethyl-N-nitrosourea (ENU) mutagenesis screens. All three models exhibit a characteristic B cell differentiation defect that manifests during the so-called transitional (T) stages of splenic B cell maturation which these cells have to pass through prior to becoming mature, antigen-reactive B cells. Whereas the T1 population is largely preserved in SPPL2a-/- mice, T2 B cells as well as subsequent stages like the mature B cells are significantly depleted. In addition to this maturation block of the follicular B cells also innate-like B cell populations like the marginal zone and B1 B cells are significantly reduced in SPPL2a-deficient mice so that these mice are characterised by a global depletion of B lymphocytes. Also the remaining B cells exhibit a major functional deficit, antibody production and humoral immune responses are significantly impaired. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2a knockout mice. Constitutive SPPL2a knockout mice are viable. Three different strains of SPPL2a-deficient mice are generated by gene targeting or derived from N-ethyl-N-nitrosourea (ENU) mutagenesis screens. All three models exhibit a characteristic B cell differentiation defect that manifests during the so-called transitional (T) stages of splenic B cell maturation which these cells have to pass through prior to becoming mature, antigen-reactive B cells. Whereas the T1 population is largely preserved in SPPL2a-/- mice, T2 B cells as well as subsequent stages like the mature B cells are significantly depleted. In addition to this maturation block of the follicular B cells also innate-like B cell populations like the marginal zone and B1 B cells are significantly reduced in SPPL2a-deficient mice so that these mice are characterised by a global depletion of B lymphocytes. Also the remaining B cells exhibit a major functional deficit, antibody production and humoral immune responses are significantly impaired. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2b knockout mice that show no obvious phenotype. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2b knockout mice that show no obvious phenotype. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2b knockout mice that show no obvious phenotype. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL2b knockout mice that show no obvious phenotype. Double knockout of SPPL2a and SPPL2b. SPPL2a/b double-deficient mice are viable, without any overt disability and exhibit the phenotypic changes associated with the loss of SPPL2a
additional information
generation of constitutive SPPL3 knockout mice from different strains
additional information
generation of constitutive SPPL3 knockout mice from different strains
additional information
generation of constitutive SPPL3 knockout mice from different strains
additional information
generation of constitutive SPPL3 knockout mice from different strains
additional information
proteolytic processing by SPPL2c impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum in recombinant SPPL2c-overexpessing HEK-293 cells. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Quantification of pre-acrosomal structures in seminiferous tubular cross sections in wild-type and SPPL2c-lacking cells
additional information
proteolytic processing by SPPL2c impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum in recombinant SPPL2c-overexpessing HEK-293 cells. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Quantification of pre-acrosomal structures in seminiferous tubular cross sections in wild-type and SPPL2c-lacking cells
additional information
generation of DELTAspp1 strains. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
additional information
-
generation of DELTAspp1 strains. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
additional information
-
generation of DELTAspp1 strains. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
-
additional information
-
generation of DELTAspp1 strains. DELTAspp1 strains do not show increased expression of fungal UPR marker genes in planta. DELTAspp1 strains are not impaired in H2O2 resistance
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
coexpression of HA-tagged enzyme SPP and fluoresecence-tagged (GFP, CFP, or YFP) substrate heme oxygenase-1 (HO-1) in HEK-293 cells
-
enzyme overexpression in Bacillus licheniformis, gene sppA is integrated into the genome
-
functional ectopic overexpressing wild-type SPPL2c and catalytically inactive SPPL2c in HEK-293 cells, induction of SPPL2c overexpression with doxycycline. Neither SPP monomer nor SPP dimer is change in SPPL2c-expressing cells compared to control cells. Endogenous SPP expression is not affected by SPPL2c overexpression. Endoplasmic reticulum and Golgi morphology in HEK-293 cells with ectopic expression of SPPL2c, overview
gene spp1 or UMAG_02729, phylogenetic tree, quantitative RT-PCR enzyme expression analysis
gene sppA, phylogenetic analysis, recombinant expression of FLAG-tagged wild-type enzyme SppA and mutant D337A SppA in the Aspergillus nidulans DELTAsppA knockout mutant strain, recombinant expression of N-terminally YFP-tagged enzyme in wild-type Aspergillus nidulans
-
gene sppA, recombinant expression of HA-tagged enzyme SppA in HeLa cells, coexpression with FKBP8
-
gene SPPL2c, based on the intronless gene architecture, SPPL2c is suggested to represent a redundant pseudogene
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
-
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
-
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome
-
spp1 belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant
spp1 belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant
spp1 belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant
-
-
spp1 belongs to the unfolded protein response (UPR) core genes identified under stringent filtering criteria and expression of spp1 is strongly induced in planta. Activation of the UPR is connected to the control of fungal proliferation through direct protein-protein interactions between the UPR regulator Cib1 and the developmental regulator Clp1. This interaction leads to functional modification of Cib1 and modulation of UPR gene expression to adapt the UPR for long-term activity in the plant
-
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
application of the photophore walking technique for probing the active sites of SPP. Nontransition state gamma-secretase inhibitors inhibit labeling of gamma-secretase by activity-based probes but enhance labeling of SPP. The opposite is true of gamma secretase modulators, which have little effect on the labeling of gamma-secretase but diminish labeling of SPP
medicine
pharmacology
mechanism of SPP inhibitors in Plasmodium falciparum, overview. PlSPP is an attractive target for the treatment of malaria
medicine
-
herpes simplex virus type 1 glycoprotein specifically binds to signal peptide peptidase SPP. SPP dominant negative mutants and shRNA against SPP significantly reduce herpes simplex virus type 1 replication in vitro. SPP also affects lysosomes and endoplasmic reticulum responses to herpes simplex virus type 1 infection
medicine
malaria heat shock protein 101 is a substrate, and partial inhibition of Plasmodium falciparum signal peptide peptidase correlates with the emergence of gametocytes
medicine
-
signal peptide peptidase SPP catalyzes the intramembrane cleavage of heme oxygenase HO-1. Coexpression of HO-1 with wild-type SPP promotes the nuclear localization of HO-1 in cells. Two adjacent intramembrane cleavage sites are located after S275 and F276 within the trans membrane segment. Mutations of S275F276 to A275L276 significantly hinder SPP-mediated cleavage and nuclear localization. Nuclear heme oxygenase-1 is detected in A549 and DU145 cancer cell lines expressing high levels of endogenous HO-1 and SPP. SPP knockdown or inhibition significantly reduces nuclear HO-1 localization in A549 and DU145 cells. The positive nuclear HO-1 stain is also evident in lung cancer tissues expressing high levels of HO-1 and SPP. Overexpression of a truncated HO-1 lacking the trans membrane segment in HeLa and H1299 cells promotes cell proliferation and migration/invasion
medicine
specific inhibition of distinct SPP/SPPL proteases is proposed as a therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections
medicine
specific inhibition of distinct SPP/SPPL proteases is proposed as a therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections
medicine
specific inhibition of distinct SPP/SPPL proteases is proposed as a therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections
medicine
specific inhibition of distinct SPP/SPPL proteases is proposed as a therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections. Scheme for potential applications of SPPL2a inhibitors, overview
medicine
-
the signal peptide peptidase hSPP is a biomedically important protease implicated as therapeutic target for hepatitis C
medicine
-
the signal peptide peptidase pSPP is a biomedically important protease implicated as therapeutic target for treatement of Plasmodia and malaria
medicine
-
the signal peptide peptidase SPPL2a is a biomedically important protease implicated as therapeutic target for B-cell immunomodulation and neoplasia
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Schrul, B.; Kapp, K.; Sinning, I.; Dobberstein, B.
Signal peptide peptidase (SPP) assembles with substrates and misfolded membrane proteins into distinct oligomeric complexes
Biochem. J.
427
523-534
2010
Homo sapiens
brenda
Gertsik, N.; Chau, D.M.; Li, Y.M.
gamma-Secretase inhibitors and modulators induce distinct conformational changes in the active sites of gamma-secretase and signal peptide peptidase
ACS Chem. Biol.
10
1925-1931
2015
Homo sapiens
brenda
Baldwin, M.; Russo, C.; Li, X.; Chishti, A.H.
Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis
Biochem. Biophys. Res. Commun.
450
1427-1432
2014
Plasmodium falciparum (C0KWU7), Plasmodium falciparum
brenda
Nam, S.E.; Paetzel, M.
Structure of signal peptide peptidase A with C-termini bound in the active sites: insights into specificity, self-processing, and regulation
Biochemistry
52
8811-8822
2013
Bacillus subtilis (O34525), Bacillus subtilis, Bacillus subtilis 168 (O34525)
brenda
Hoshi, M.; Ohki, Y.; Ito, K.; Tomita, T.; Iwatsubo, T.; Ishimaru, Y.; Abe, K.; Asakura, T.
Experimental detection of proteolytic activity in a signal peptide peptidase of Arabidopsis thaliana
BMC Biochem.
14
16
2013
Arabidopsis thaliana (O81062), Arabidopsis thaliana
brenda
Chen, C.Y.; Malchus, N.S.; Hehn, B.; Stelzer, W.; Avci, D.; Langosch, D.; Lemberg, M.K.
Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u
EMBO J.
33
2492-2506
2014
Homo sapiens
brenda
Nam, S.E.; Kim, A.C.; Paetzel, M.
Crystal structure of Bacillus subtilis signal peptide peptidase A
J. Mol. Biol.
419
347-358
2012
Bacillus subtilis (O34525), Bacillus subtilis, Bacillus subtilis 168 (O34525)
brenda
Hsu, F.F.; Yeh, C.T.; Sun, Y.J.; Chiang, M.T.; Lan, W.M.; Li, F.A.; Lee, W.H.; Chau, L.Y.
Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity
Oncogene
34
2360-2370
2015
Homo sapiens
brenda
Moss, C.X.; Brown, E.; Hamilton, A.; Van der Veken, P.; Augustyns, K.; Mottram, J.C.
An essential signal peptide peptidase identified in an RNAi screen of serine peptidases of Trypanosoma brucei
PLoS ONE
10
e0123241
2015
Trypanosoma brucei
brenda
Allen, S.J.; Mott, K.R.; Matsuura, Y.; Moriishi, K.; Kousoulas, K.G.; Ghiasi, H.
Binding of HSV-1 glycoprotein K (gK) to signal peptide peptidase (SPP) is required for virus infectivity
PLoS ONE
9
e85360
2014
Homo sapiens
brenda
Mentrup, T.; Loock, A.C.; Fluhrer, R.; Schroeder, B.
Signal peptide peptidase and SPP-like proteases - possible therapeutic targets?
Biochim. Biophys. Acta
1864
2169-2182
2017
Mus musculus (Q3TD49), Mus musculus (Q9CUS9), Mus musculus (Q9D8V0), Mus musculus (Q9JJF9), Plasmodium falciparum (Q8IKQ9), Homo sapiens (Q8IUH8)
brenda
Yuecel, S.S.; Stelzer, W.; Lorenzoni, A.; Wozny, M.; Langosch, D.; Lemberg, M.K.
The metastable XBP1u transmembrane domain defines determinants for intramembrane proteolysis by signal peptide peptidase
Cell Rep.
26
3087-3099.e11
2019
Homo sapiens
brenda
Papadopoulou, A.A.; Mueller, S.A.; Mentrup, T.; Shmueli, M.D.; Niemeyer, J.; Haug-Kroeper, M.; von Blume, J.; Mayerhofer, A.; Feederle, R.; Schroeder, B.; Lichtenthaler, S.F.; Fluhrer, R.
Signal peptide peptidase-Like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins
EMBO Rep.
20
e46451
2019
Mus musculus (A2A6C4)
brenda
Papadopoulou, A.A.; Mueller, S.A.; Mentrup, T.; Shmueli, M.D.; Niemeyer, J.; Haug-Kroeper, M.; von Blume, J.; Mayerhofer, A.; Feederle, R.; Schroeder, B.; Lichtenthaler, S.F.; Fluhrer, R.
Signal peptide peptidase-Like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins
EMBO Rep.
20
e46451
2019
Mus musculus (A2A6C4), Homo sapiens (Q8IUH8)
brenda
Velcicky, J.; Bodendorf, U.; Rigollier, P.; Epple, R.; Beisner, D.R.; Guerini, D.; Smith, P.; Liu, B.; Feifel, R.; Wipfli, P.; Aichholz, R.; Couttet, P.; Dix, I.; Widmer, T.; Wen, B.; Brandl, T.
Discovery of the first potent, selective, and orally bioavailable signal peptide peptidase-like 2a (SPPL2a) inhibitor displaying pronounced immunomodulatory effects in vivo
J. Med. Chem.
61
865-880
2018
Rattus norvegicus (D3ZNG3), Homo sapiens (Q8TCT8), Mus musculus (Q9JJF9), Mus musculus
brenda
Cai, D.; Wang, H.; He, P.; Zhu, C.; Wang, Q.; Wei, X.; Nomura, C.T.; Chen, S.
A novel strategy to improve protein secretion via overexpression of the SppA signal peptide peptidase in Bacillus licheniformis
Microb. Cell Fact.
16
70
2017
Bacillus licheniformis, Bacillus licheniformis BL10
brenda
Bat-Ochir, C.; Kwak, J.Y.; Koh, S.K.; Jeon, M.H.; Chung, D.; Lee, Y.W.; Chae, S.K.
The signal peptide peptidase SppA is involved in sterol regulatory element-binding protein cleavage and hypoxia adaptation in Aspergillus nidulans
Mol. Microbiol.
100
635-655
2016
Aspergillus nidulans, Aspergillus nidulans A773
brenda
Hsu, F.F.; Chou, Y.T.; Chiang, M.T.; Li, F.A.; Yeh, C.T.; Lee, W.H.; Chau, L.Y.
Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation
Oncogene
38
1688-1701
2019
Homo sapiens
brenda
Ran, Y.; Ladd, G.Z.; Ceballos-Diaz, C.; Jung, J.I.; Greenbaum, D.; Felsenstein, K.M.; Golde, T.E.
Differential inhibition of signal peptide peptidase family members by established gamma-secretase inhibitors
PLoS ONE
10
e0128619
2015
Homo sapiens, Mus musculus, Plasmodium sp.
brenda
Schaefer, B.; Moriishi, K.; Behrends, S.
Insights into the mechanism of isoenzyme-specific signal peptide peptidase-mediated translocation of heme oxygenase
PLoS ONE
12
e0188344
2017
Homo sapiens
brenda
Plegge, T.; Spiegel, M.; Krueger, N.; Nehlmeier, I.; Winkler, M.; Gonzalez Hernandez, M.; Poehlmann, S.
Inhibitors of signal peptide peptidase and subtilisin/kexin-isozyme 1 inhibit Ebola virus glycoprotein-driven cell entry by interfering with activity and cellular localization of endosomal cathepsins
PLoS ONE
14
e0214968
2019
Homo sapiens
brenda
Pinter, N.; Hach, C.A.; Hampel, M.; Rekhter, D.; Zienkiewicz, K.; Feussner, I.; Poehlein, A.; Daniel, R.; Finkernagel, F.; Heimel, K.
Signal peptide peptidase activity connects the unfolded protein response to plant defense suppression by Ustilago maydis
PLoS Pathog.
15
e1007734
2019
Ustilago maydis (A0A0D1E4M7), Ustilago maydis, Ustilago maydis 521 (A0A0D1E4M7), Ustilago maydis FGSC 9021 (A0A0D1E4M7)
brenda
Shi, X.; Botting, C.H.; Li, P.; Niglas, M.; Brennan, B.; Shirran, S.L.; Szemiel, A.M.; Elliott, R.M.
Bunyamwera orthobunyavirus glycoprotein precursor is processed by cellular signal peptidase and signal peptide peptidase
Proc. Natl. Acad. Sci. USA
113
8825-8830
2016
Homo sapiens
brenda
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