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Information on EC 3.4.23.B24 - signal peptide peptidase and Organism(s) Homo sapiens and UniProt Accession Q8IUH8
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: Homo sapiens
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
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
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
-
-
?
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
-
-
?
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
-
-
?
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
?
-
-
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
?
-
-
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
-
-
?
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
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
-
-
?
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
reversible, inhibits CD74/p8 processing in vivo and spares gamma-secretase activity
-
(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-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
-
i.e. Compound E
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
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
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
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
-
increasing the rigidity of the transmembrane helices prevents SPP-catalyzed cleavage
-
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
0.000519 - 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
0.000519
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
0.006
2,2'-(2-oxo-1,3-propanediyl)bis[N-[(phenylmethoxy)carbonyl]-L-leucyl-L-leucinamide]
Homo sapiens
pH 7.4, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
overexpressed SPPL2c localises to the endoplasmic reticulum
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
malfunction
physiological function
additional information
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
-
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
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
-
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
-
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-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
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
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). SPP2C_HUMAN
684
0
74503
Swiss-Prot
other Location (Reliability: 4)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
SPP/SPPL proteases either act as mono- or homodimers
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
-
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
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
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene SPPL2c, based on the intronless gene architecture, SPPL2c is suggested to represent a redundant pseudogene
coexpression of HA-tagged enzyme SPP and fluoresecence-tagged (GFP, CFP, or YFP) substrate heme oxygenase-1 (HO-1) in HEK-293 cells
-
gene sppA, recombinant expression of HA-tagged enzyme SppA in HeLa cells, coexpression with FKBP8
-
recombinant expression of FLAG-tagged enzyme in HEK-293T cells, coexpression with FLAG-tagged substrate FBA
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome
-
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
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
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
-
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
-
the signal peptide peptidase hSPP is a biomedically important protease implicated as therapeutic target for hepatitis C
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
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
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
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
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
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)
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
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)
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
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.
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
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
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