3.4.23.B24: signal peptide peptidase
This is an abbreviated version!
For detailed information about signal peptide peptidase, go to the full flat file.
Word Map on EC 3.4.23.B24
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3.4.23.B24
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aspartyl
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presenilins
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intramembrane-cleaving
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gamma-secretase
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sppl2a
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medicine
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gxgd-type
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spp-mediated
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bri2
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i-clips
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presenilin-like
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site-2
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pharmacology
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analysis
- 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
Reaction
intramembrane cleavage of signal peptides =
Synonyms
ANID_08681, aspartic intramembrane protease, Hm13, hSPP, minor histocompatibility antigen H13, PF3D7_1457000, PlSPP, signal peptide peptidase like 2a, signal peptide peptidase-like 2a, signal peptide peptidase-like 2B, signal peptide peptidase-like 2C, signal peptide peptidase-like 3, SPP, SPP-like 2A, SPP-like 2B, SPP-like 2C, SPP-like 3, SPP1, SppA, SPPL, SPPL2a, SPPL2b, SPPL2c, UMAG_02729
ECTree
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General Information
General Information on EC 3.4.23.B24 - signal peptide peptidase
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evolution
malfunction
metabolism
physiological function
additional information
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similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
evolution
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similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
evolution
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similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase
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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
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depletion of SPPL2a leads to accumulation of an NH2-terminal fragment (NTF) of CD74 which impairs B cell development and survival
malfunction
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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
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increasing the rigidity of the transmembrane helices prevents SPP-catalyzed cleavage. The C-terminal di-glycine XBP1u mutants show local TM helix destabilization
malfunction
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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
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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
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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
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malfunction
Aspergillus nidulans A773
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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
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malfunction
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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
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malfunction
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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
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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
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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
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metabolism
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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physiological function
Aspergillus nidulans A773
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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
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physiological function
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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
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physiological function
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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
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endogenous SPP expression is not affected by human SPPL2c overexpression
additional information
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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