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Information on EC 3.4.23.B24 - signal peptide peptidase and Organism(s) Mus musculus and UniProt Accession Q9D8V0
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 taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SPPL2a
SPPL2b
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
-
-
?
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
-
-
?
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
-
-
?
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
?
-
-
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
-
-
?
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
-
-
?
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
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
DBZ
(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
-
-
(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
-
-
(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
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
DBZ
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]
(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
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 N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752
-
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 N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752
-
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 N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752
-
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 N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT), semagacestat, avagacestat, and MK-0752
-
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 (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
-
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)
-
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)
-
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)
-
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)
-
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)
-
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 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)
-
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 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)
-
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 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)
-
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 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)
-
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 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 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 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 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)
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000177 - 0.00214
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
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
0.00214
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
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high SPPL2b expression rate
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
overexpressed SPP localises to the endoplasmic reticulum
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
evolution
-
similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
malfunction
physiological function
malfunction
-
depletion of SPPL2a leads to accumulation of an NH2-terminal fragment (NTF) of CD74 which impairs B cell development and survival
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
physiological function
involvement of SPPL2c in acrosome formation during spermatogenesis
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
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
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). SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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 SPPL2a is a biomedically important protease implicated as therapeutic target for B-cell immunomodulation and neoplasia
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
Homo sapiens (Q8IUH8), Mus musculus (Q3TD49), Mus musculus (Q9CUS9), Mus musculus (Q9D8V0), Mus musculus (Q9JJF9), Plasmodium falciparum (Q8IKQ9)
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)
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)
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
Homo sapiens (Q8TCT8), Mus musculus (Q9JJF9), Mus musculus, Rattus norvegicus (D3ZNG3)
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