SPCS2 (signal peptidase complex subunit 2, also SPC25, the microsomal signal peptidase 25 kDa subunit) is a 226 aa multi-pass endoplasmic reticulum membrane protein that is one of the three non-catalytic accessory subunits (with SPCS1 and SPCS3) of the eukaryotic ER signal peptidase complex (SPC). The SPC removes N-terminal signal sequences from secretory and membrane preproteins as they are translocated into the ER lumen; catalysis resides in the SEC11A or SEC11C subunits. SPCS2 spans the ER membrane twice with both termini facing the cytosol and is thought to enhance the enzymatic activity of the complex and to facilitate interactions between components of the translocation site. Together with the other subunits it helps form the transmembrane window that locally thins the ER bilayer, contributing to the complex's selectivity for signal-peptide hydrophobic regions shorter than about 18-20 residues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005787
signal peptidase complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SPCS2 is a constitutive accessory subunit of the ER signal peptidase complex; the phylogenetic assignment reflects its core identity.
Reason: Core complex membership, supported experimentally by cryo-EM and ComplexPortal curation.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3
|
|
GO:0045047
protein targeting to ER
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: SPCS2 does not target proteins to the ER; as part of the signal peptidase complex it acts on already-translocating substrates to cleave the signal peptide. The phylogenetic term is mis-specified; the accurate process is signal peptide processing.
Reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465).
Proposed replacements:
signal peptide processing
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum
|
|
GO:0005787
signal peptidase complex
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro-based electronic assignment to the signal peptidase complex, consistent with experimental evidence.
Reason: Correct core complex membership; redundant with experimental IPI/IBA evidence.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3
|
|
GO:0005789
endoplasmic reticulum membrane
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: SPCS2 is a multi-pass ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization.
Reason: Core localization, supported by structure (PMID:34388369) and ortholog topology.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: Generic membrane localization, a parent of the more informative ER membrane term.
Reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SPCS2 localization.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
Multi-pass membrane protein
|
|
GO:0005515
protein binding
|
IPI
PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho... |
KEEP AS NON CORE |
Summary: High-throughput coronavirus interactome capturing an interaction between SPCS2 and the SARS-CoV-2 spike protein; the bare protein binding term is uninformative.
Reason: High-throughput host-pathogen interaction; bare protein binding is uninformative and not the core function.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
Q15005; P0DTC2: S; Xeno
|
|
GO:0005787
signal peptidase complex
|
IPI
PMID:34388369 Structure of the human signal peptidase complex reveals the ... |
ACCEPT |
Summary: ComplexPortal annotation of SPCS2 as a component of the signal peptidase complex, based on the cryo-EM structure of the human SPC.
Reason: Definitive experimental (structural) evidence for SPC membership; the core identity of SPCS2.
Supporting Evidence:
PMID:34388369
the human SPC exists in two functional paralogs with distinct proteolytic subunits
|
|
GO:0005789
endoplasmic reticulum membrane
|
IDA
PMID:34388369 Structure of the human signal peptidase complex reveals the ... |
ACCEPT |
Summary: Direct (structural) evidence places SPCS2 in the ER membrane as part of the SPC; correct core localization.
Reason: IDA-supported ER membrane localization consistent with the membrane-embedded SPC structure.
Supporting Evidence:
PMID:34388369
a transmembrane window collectively formed by all subunits locally thins the bilayer
|
|
GO:0016485
protein processing
|
IDA
PMID:34388369 Structure of the human signal peptidase complex reveals the ... |
ACCEPT |
Summary: SPCS2 participates in proteolytic processing of preproteins as part of the signal peptidase complex; the more precise term is signal peptide processing (GO:0006465).
Reason: Correct involvement in the SPC's proteolytic processing of substrates; supported by the structural study and ComplexPortal curation. The core process is signal peptide processing.
Supporting Evidence:
PMID:34388369
the determinants for signal peptide cleavage
|
|
GO:0005789
endoplasmic reticulum membrane
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Sequence-similarity transfer of ER membrane localization from an ortholog; consistent with stronger experimental evidence.
Reason: Correct core localization, redundant with IDA/IEA evidence.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
|
|
GO:0005515
protein binding
|
IPI
PMID:34388369 Structure of the human signal peptidase complex reveals the ... |
KEEP AS NON CORE |
Summary: Interactions with the other SPC subunits (SEC11A/SEC11C, SPCS1, SPCS3) captured during the structural study; bare protein binding is uninformative although the intra-complex interactions are genuine.
Reason: Real intra-complex interactions but bare protein binding is uninformative; the SPC membership is already captured by GO:0005787.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
Within the complex, interacts with SEC11A or SEC11C and SPCS1
|
|
GO:0005789
endoplasmic reticulum membrane
|
TAS
Reactome:R-HSA-422051 |
ACCEPT |
Summary: Reactome curation of SPCS2 ER membrane localization (preproghrelin signal peptide cleavage context).
Reason: Correct core localization; redundant with experimental evidence.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
|
|
GO:0005789
endoplasmic reticulum membrane
|
TAS
Reactome:R-HSA-9918795 |
ACCEPT |
Summary: Reactome curation of SPCS2 ER membrane localization (flavivirus signalase cleavage context).
Reason: Correct core localization; redundant with experimental evidence.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
|
|
GO:0005789
endoplasmic reticulum membrane
|
TAS
Reactome:R-HSA-9918871 |
ACCEPT |
Summary: Reactome curation of SPCS2 ER membrane localization (signalase cleavage context).
Reason: Correct core localization; redundant with experimental evidence.
Supporting Evidence:
file:human/SPCS2/SPCS2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
|
Q: How does SPCS2 enhance the enzymatic activity of the signal peptidase complex - through stabilization of the catalytic SEC11 subunit, substrate gating, or coupling to the Sec61 translocon?
Q: Is SPCS2 strictly required for SPC assembly and signal-peptide cleavage in human cells, or is it conditionally dispensable like SPCS1?
Experiment: Compare cleavage kinetics of reconstituted SPC with and without SPCS2 to quantify its proposed activity-enhancing role and substrate-length dependence.
Experiment: Acute SPCS2 depletion followed by quantitative N-terminomics and translocon proximity proteomics to test whether SPCS2 organizes translocation-site interactions in cells.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The requested target—UniProt Q15005—corresponds to human SPCS2 (signal peptidase complex subunit 2), also known as SPC25 / KIAA0102. This identity is consistent with an independent target registry (Open Targets) listing approved symbol SPCS2 and approved name “signal peptidase complex subunit 2” (ENSG00000118363). (OpenTargets Search: -SPCS2)
The signal peptidase complex (SPC) is an essential endoplasmic reticulum (ER) membrane complex that cleaves signal peptides from secretory and membrane proteins entering the secretory pathway. In eukaryotes, SPC is described as a four-subunit complex consisting of SPCS1, SPCS2, SPCS3, and Sec11. In mammals, Sec11 is represented by two paralogous catalytic subunits, SEC11A or SEC11C, forming two SPC variants. (chung2024spc2modulatessubstrate pages 1-2, kozono2023cleavageofthe pages 1-4)
SPCS2 is generally described as a non-catalytic / accessory SPC subunit, distinct from the catalytic subunits (SEC11A/SEC11C) and a proposed catalytic “core” involving SEC11A/C and SPCS3. (zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60)
Beyond canonical N-terminal signal peptide cleavage, recent work supports an expanded role for SPC in post-translocational “quality control” cleavage of cryptic/noncanonical sites in certain membrane proteins—often exposed by misfolding or failed assembly—thereby linking SPC processing to ER protein quality control and degradation pathways. (zanotti2023characterisationofthe pages 57-60, zanotti2023characterisationofthe pages 38-43, zanotti2023characterisationofthe pages 30-34)
SPCS2 is not itself the catalytic peptidase; rather, mechanistic work (in yeast Spc2 and extrapolated via structural conservation to human SPCS2) indicates that Spc2/SPCS2 modulates substrate discrimination and cleavage-site selection by the SPC. Specifically, loss or mutation of Spc2 compromises substrate discrimination and cleavage-site identification. (chung2024spc2modulatessubstrate pages 1-2)
A proposed mechanism is that Spc2/SPCS2 helps shape the local membrane environment—promoting “membrane thinning” at the SPC center—thereby affecting how signal peptides with different hydrophobic segment properties are positioned for cleavage. (chung2024spc2modulatessubstrate pages 1-2)
A key mechanistic concept is the functional coupling of SPC to co-translational translocation at the ER. Spc2/SPCS2 has been reported to mediate transient interactions with the Sec61 translocon via the Sec61 β subunit, consistent with a role in coordinating signal peptide cleavage with translocation. (chung2024spc2modulatessubstrate pages 1-2)
SPCS2 is a membrane subunit of the ER-localized SPC. Structural/topological inference indicates Spc2/SPCS2 contributes substantially to the cytosolic face of the SPC and includes transmembrane helices as part of the complex’s membrane architecture. (chung2024spc2modulatessubstrate pages 1-2, chung2024spc2modulatessubstrate pages 2-3)
A 2024 Journal of Cell Biology study in yeast directly examined Spc2 function and emphasized conservation to human SPCS2 (noting structural similarity and that human SPCS2 constitutes much of the cytosolic SPC portion). The study concluded that Spc2 influences substrate selection and cleavage-site recognition, supported by experiments across signal sequence variants and complemented strains; experiments were performed with replication (e.g., n = 3 per data point in specific assays). (chung2024spc2modulatessubstrate pages 4-4, chung2024spc2modulatessubstrate pages 2-3)
Although conducted in yeast, it is one of the most direct recent mechanistic sources relevant to human SPCS2 due to explicit structural cross-referencing of human SPCS2. (chung2024spc2modulatessubstrate pages 1-2, chung2024spc2modulatessubstrate pages 2-3)
A 2023 Journal of Cell Science study identified Jaw1 (IRAG2/LRMP) as a noncanonical SPC substrate: Jaw1’s C-terminal region is cleaved after insertion by the SPC, and the SEC11A-containing SPC (but not SEC11C-containing SPC) specifically cleaves Jaw1. Functionally, cleavage enhanced Jaw1’s augmentative effect on IP3 receptor–mediated Ca2+ release, linking SPC activity to ER Ca2+ signaling phenotypes. (kozono2023cleavageofthe pages 1-4)
This work does not assign a unique role to SPCS2, but it is directly relevant because SPCS2 is one of the accessory subunits of the human SPC complexes executing this cleavage. (kozono2023cleavageofthe pages 1-4)
A 2023 research thesis presents a detailed model of the human SPC as a quality-control enzyme cleaving cryptic sites in membrane proteins. It provides experimentally supported examples (connexins such as Cx32, iRhom2, and Hrd1 contexts) and argues that SPC can act post-translationally when cryptic sites become accessible. In this framework, SPCS2 (alongside SPCS1 and SPCS3) affects noncanonical cleavage “to varying extents,” and removal of individual subunits can destabilize the complex. (zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60)
This work also reports quantitative/statistical elements for certain substrates (e.g., iRhom2 cleavage quantification with n = 3–6 and significance thresholds; Cx32C201R cleavage quantification n = 3 with significance markers). (zanotti2023characterisationofthe pages 38-43)
A key practical tool for SPC biology is cavinafungin, described as an inhibitor of SPC catalytic subunits (SEC11A/SEC11C) and reported to cause a complete block of noncanonical cleavage in the cited human SPC quality-control work. (zanotti2023characterisationofthe pages 57-60)
While cavinafungin is not SPCS2-specific, it is the main small-molecule tool in the retrieved evidence for perturbing SPCS2-containing SPC complexes and is discussed as a route to block SPC-dependent processing. (zanotti2023characterisationofthe pages 26-30, zanotti2023characterisationofthe pages 57-60)
Multiple virus-focused studies implicate the SPC (including SPCS2) as a host machinery engaged by viral proteins:
These findings support the real-world relevance of SPCS2-containing SPC complexes in viral glycoprotein maturation/assembly contexts at the ER. (chen2021comprehensiveanalysisof pages 8-11, matthaei2024landscapeofproteinprotein pages 14-16)
The 2024 mechanistic study and the 2023 quality-control framework converge on an interpretation that SPCS2 is an accessory factor shaping how SPC engages substrates: SPCS2 contributes to the architecture and cytosolic face of the complex and modulates how cleavage sites are selected—likely by coordinating with Sec61-mediated translocation and membrane-shaping effects—rather than providing catalytic residues itself. (chung2024spc2modulatessubstrate pages 1-2, zanotti2023characterisationofthe pages 53-57)
Recent work emphasizes that SPC may serve as a broader ER protease involved in noncanonical cleavage of membrane proteins (including substrates that are not classical secretory precursors), with physiological outcomes such as altered Ca2+ signaling (Jaw1) and potential coupling to ERAD. (kozono2023cleavageofthe pages 1-4, zanotti2023characterisationofthe pages 57-60)
Open Targets lists SPCS2 associations with several diseases/traits with modest-to-moderate association scores, including neurodegenerative disease (0.5271), dengue disease (0.4629), and type 2 diabetes mellitus (0.2845) (as well as alcohol drinking and abruptio placentae with lower scores). (OpenTargets Search: -SPCS2)
These are aggregated associations and should be interpreted as hypothesis-generating rather than direct mechanistic attribution to SPCS2. (OpenTargets Search: -SPCS2)
A pooled genome-wide CRISPR/Cas9 screen in human trophoblasts (Jeg-3) identified signal peptide processing genes including SPCS2 as part of enriched host factors “crucial for ZIKV replication,” although the provided excerpt does not include per-gene effect sizes for SPCS2. (rother2021signalpeptidasecomplex pages 1-2)
A CRISPR screen in murine lung adenocarcinoma models identified SPCS2 among genes reaching significance in Keap1-mutant dependency analysis, and gene set enrichment on differential gene scores indicated enrichment of ER stress/UPR pathways (FDR = 0.0073). (romero2020keap1mutationrenders pages 2-4)
The following table compiles key concepts, evidence types, quantitative details, and primary sources.
| Topic | Key claim | Evidence type | Specific quantitative/statistical detail if available | Source with year and URL/DOI |
|---|---|---|---|---|
| Identity / complex membership | Human SPCS2 (UniProt Q15005) is the signal peptidase complex subunit 2, a conserved non-catalytic/accessory subunit of the ER signal peptidase complex (SPC), which in higher eukaryotes contains SPCS1, SPCS2, SPCS3, and either SEC11A or SEC11C. Structural/functional work places SPCS2 outside the SEC11A/C+SPCS3 catalytic core. (chung2024spc2modulatessubstrate pages 1-2, zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60) | Structure; comparative cell biology; complex biochemistry | No direct human stoichiometric value reported in the cited excerpts; two SPC paralogs distinguished by SEC11A vs SEC11C. (chung2024spc2modulatessubstrate pages 1-2, zanotti2023characterisationofthe pages 57-60) | Chung et al., 2024, https://doi.org/10.1083/jcb.202211035; Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
| Localization / topology | SPCS2 is an ER membrane component of SPC. Conserved structural analysis indicates Spc2/SPCS2 contributes much of the cytosolic face of the complex and includes additional transmembrane helices; SPC catalysis occurs at the ER lumenal side near the membrane. (chung2024spc2modulatessubstrate pages 1-2, zanotti2023characterisationofthe pages 57-60, chung2024spc2modulatessubstrate pages 2-3) | Structure; topology inference; comparative modeling | In yeast-based comparative analysis, human SPCS2 was noted to be structurally conserved with yeast Spc2 and to constitute most of the cytosolic part of SPC. (chung2024spc2modulatessubstrate pages 2-3) | Chung et al., 2024, https://doi.org/10.1083/jcb.202211035; Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
| Mechanistic role | SPCS2/Spc2 helps determine substrate discrimination and cleavage-site selection by SPC, likely by promoting local membrane thinning and by presenting features of signal peptides/signal anchors to the complex. In mammals and yeast, Spc2/SPCS2 is also reported to mediate transient interaction with the Sec61 translocon via Sec61β. (chung2024spc2modulatessubstrate pages 1-2, zanotti2023characterisationofthe pages 53-57, chung2024spc2modulatessubstrate pages 3-4, chung2024spc2modulatessubstrate pages 2-3) | Genetics/mutagenesis; computational/MD; structure | Yeast functional data: Spc2 promotes cleavage of signal sequences with short n-regions and reduces cleavage of long n-region substrates; N# >16 substrates were more efficiently cleaved when Spc2 was absent or C-terminally truncated; at least n=3 independent replicates/data point in cited figure context; ~10% reduction in Sec11 and Spc3 abundance in spc2Δ cells in one quantitative analysis. (chung2024spc2modulatessubstrate pages 4-4, chung2024spc2modulatessubstrate pages 3-4, chung2024spc2modulatessubstrate pages 2-3) | Chung et al., 2024, https://doi.org/10.1083/jcb.202211035; Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
| Noncanonical substrates / quality control | Beyond canonical signal peptide removal, human SPC participates in ER quality control by cleaving cryptic/noncanonical sites in membrane proteins; SPCS2 affects this process to varying extents, although SPCS1 appears more central as a recruitment/exosite factor. Validated or discussed substrates include Cx32, Cx26, Cx30.3, iRhom2, Hrd1, and Jaw1/IRAG2. (zanotti2023characterisationofthe pages 53-57, zanotti2023characterisationofthe pages 57-60, zanotti2023characterisationofthe pages 38-43, kozono2023cleavageofthe pages 1-4, zanotti2023characterisationofthe pages 30-34) | Biochemistry; knockdown/KO; pulse-chase; inhibitor studies | Computational screening identified 262 membrane proteins with putative N-terminal cryptic SPC sites in one filtered set and ~1300 candidate proteins in a broader screen; iRhom2 cleavage quantification was reported with n=3–6 and significance markers P<0.05, P<0.001; Cx32C201R cleavage quantification n=3 with *P<0.05, P<0.01; post-translational Cx32C201R processing initiated ~30 min after synthesis. (zanotti2023characterisationofthe pages 26-30, zanotti2023characterisationofthe pages 38-43, zanotti2023characterisationofthe pages 30-34) | Zanotti, 2023, https://doi.org/10.11588/heidok.00033417; Kozono et al., 2023, https://doi.org/10.1242/jcs.260439 |
| Catalytic paralog specificity | Some noncanonical substrates show catalytic paralog selectivity: Jaw1/IRAG2 is cleaved by the SEC11A-containing SPC, not SEC11C. For Cx32, SEC11A knockdown did not block cleavage, consistent with possible compensation by SEC11C; cavinafungin blocked cleavage, indicating catalytic SPC dependence. SPCS2 is listed as an accessory component in these pathways. (kozono2023cleavageofthe pages 1-4, zanotti2023characterisationofthe pages 57-60) | Biochemistry; knockdown; pharmacology | SEC11A depletion alone did not impair Cx32 cleavage in cited experiments; cavinafungin caused a complete block of noncanonical cleavage. (zanotti2023characterisationofthe pages 57-60) | Kozono et al., 2023, https://doi.org/10.1242/jcs.260439; Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
| Viral interactions | SPCS2 is repeatedly identified as a host factor/interactor for viral proteins processed or assembled at the ER. In SARS-CoV-2 host–virus interactome studies, spike protein significantly bound the signal peptidase complex including SPCS2. In HCV AP-MS studies, SPCS2 interacted with both p7 and E2. (chen2021comprehensiveanalysisof pages 39-40, chen2021comprehensiveanalysisof pages 8-11, matthaei2024landscapeofproteinprotein pages 1-2, matthaei2024landscapeofproteinprotein pages 11-14, matthaei2024landscapeofproteinprotein pages 14-16) | AP-MS interactome; proximity labeling / affinity purification | HCV study scale: 12 p7 binders, 7 primary E2 interactors, and 24 NS4B interactors were detected; SPCS2 was among the host proteins interacting with both p7 and E2. SARS-CoV-2 interactome used SFB-TAP and BioID2 mapping approaches. (chen2021comprehensiveanalysisof pages 39-40, matthaei2024landscapeofproteinprotein pages 1-2) | Chen et al., 2021, https://doi.org/10.1101/2020.12.31.424961 and https://doi.org/10.15252/embj.2021107776; Matthaei et al., 2024, https://doi.org/10.1128/spectrum.02562-22 |
| Inhibition / therapeutic angle | SPC catalytic activity can be chemically inhibited by cavinafungin, which experimentally abolishes noncanonical SPC cleavage and is discussed as a way to perturb viral protein maturation and SPC-dependent processing. This is a catalytic SPC/SEC11 inhibitor, not an SPCS2-specific inhibitor, but it is directly relevant to SPCS2-containing complexes. (zanotti2023characterisationofthe pages 26-30, zanotti2023characterisationofthe pages 57-60) | Pharmacology; substrate-processing assays | Cavinafungin produced a “complete block” of Cx32/noncanonical cleavage in the cited human SPC quality-control work. (zanotti2023characterisationofthe pages 26-30, zanotti2023characterisationofthe pages 57-60) | Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
| Disease / translational associations | Disease linkage for SPCS2 itself is presently indirect in the cited evidence: Open Targets lists modest disease associations including dengue disease (score 0.4629), neurodegenerative disease (0.5271), type 2 diabetes mellitus (0.2845), alcohol drinking (0.0527), and abruptio placentae (0.0483), but these appear evidence-aggregated rather than gene-specific mechanistic validation. In membrane-protein QC, SPC activity is relevant to disease-linked Cx32 mutants (>200 known variants reported for Cx32 in the cited thesis). (OpenTargets Search: -SPCS2, zanotti2023characterisationofthe pages 26-30) | Database aggregation; disease-substrate functional context | Open Targets evidence counts shown as 5 for each listed association; association scores: neurodegenerative disease 0.5271, dengue disease 0.4629, T2DM 0.2845, alcohol drinking 0.0527, abruptio placentae 0.0483. Cx32 noted to have >200 disease-linked variants. (OpenTargets Search: -SPCS2, zanotti2023characterisationofthe pages 26-30) | Open Targets context (OpenTargets Search: -SPCS2); Zanotti, 2023, https://doi.org/10.11588/heidok.00033417 |
Table: This table summarizes the best-supported findings about human SPCS2 and the ER signal peptidase complex from the cited context. It highlights what is directly known for SPCS2 versus what is inferred from SPC-wide, structural, and comparative studies.
References
(OpenTargets Search: -SPCS2): Open Targets Query (-SPCS2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(chung2024spc2modulatessubstrate pages 1-2): Yeonji Chung, Chewon Yim, Gilberto P. Pereira, Sungjoon Son, Lisbeth R. Kjølbye, Lauren E. Mazurkiewicz, Amy M. Weeks, Friedrich Förster, Gunnar von Heijne, Paulo C.T. Souza, and Hyun Kim. Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex. Journal of Cell Biology, Nov 2024. URL: https://doi.org/10.1083/jcb.202211035, doi:10.1083/jcb.202211035. This article has 4 citations and is from a highest quality peer-reviewed journal.
(kozono2023cleavageofthe pages 1-4): Takuma Kozono, Chifuyu Jogano, Wataru Okumura, Hiroyuki Sato, Hitomi Matsui, Tsubasa Takagi, Nobuaki Okumura, Toshifumi Takao, Takashi Tonozuka, and Atsushi Nishikawa. Cleavage of the jaw1 c-terminal region enhances its augmentative effect on the ca2+ release via ip3 receptors. Journal of cell science, Feb 2023. URL: https://doi.org/10.1242/jcs.260439, doi:10.1242/jcs.260439. This article has 4 citations and is from a domain leading peer-reviewed journal.
(zanotti2023characterisationofthe pages 53-57): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(zanotti2023characterisationofthe pages 57-60): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(zanotti2023characterisationofthe pages 38-43): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(zanotti2023characterisationofthe pages 30-34): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(chung2024spc2modulatessubstrate pages 2-3): Yeonji Chung, Chewon Yim, Gilberto P. Pereira, Sungjoon Son, Lisbeth R. Kjølbye, Lauren E. Mazurkiewicz, Amy M. Weeks, Friedrich Förster, Gunnar von Heijne, Paulo C.T. Souza, and Hyun Kim. Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex. Journal of Cell Biology, Nov 2024. URL: https://doi.org/10.1083/jcb.202211035, doi:10.1083/jcb.202211035. This article has 4 citations and is from a highest quality peer-reviewed journal.
(chung2024spc2modulatessubstrate pages 4-4): Yeonji Chung, Chewon Yim, Gilberto P. Pereira, Sungjoon Son, Lisbeth R. Kjølbye, Lauren E. Mazurkiewicz, Amy M. Weeks, Friedrich Förster, Gunnar von Heijne, Paulo C.T. Souza, and Hyun Kim. Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex. Journal of Cell Biology, Nov 2024. URL: https://doi.org/10.1083/jcb.202211035, doi:10.1083/jcb.202211035. This article has 4 citations and is from a highest quality peer-reviewed journal.
(zanotti2023characterisationofthe pages 26-30): Andrea Zanotti. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. Text, Jan 2023. URL: https://doi.org/10.11588/heidok.00033417, doi:10.11588/heidok.00033417. This article has 0 citations and is from a peer-reviewed journal.
(chen2021comprehensiveanalysisof pages 8-11): Zhen Chen, Chao Wang, Xu Feng, Litong Nie, Mengfan Tang, Huimin Zhang, Yun Xiong, Samuel K. Swisher, Mrinal Srivastava, and Junjie Chen. Comprehensive analysis of the host-virus interactome of sars-cov-2. bioRxiv, Jan 2021. URL: https://doi.org/10.1101/2020.12.31.424961, doi:10.1101/2020.12.31.424961. This article has 19 citations.
(matthaei2024landscapeofproteinprotein pages 14-16): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
(rother2021signalpeptidasecomplex pages 1-2): Marion Rother and Michael Naumann. Signal peptidase complex subunit 1 is an essential zika virus host factor in placental trophoblasts. Apr 2021. URL: https://doi.org/10.1016/j.virusres.2021.198338, doi:10.1016/j.virusres.2021.198338. This article has 4 citations and is from a peer-reviewed journal.
(romero2020keap1mutationrenders pages 2-4): Rodrigo Romero, Francisco J. Sánchez-Rivera, Peter M. K. Westcott, Kim L. Mercer, Arjun Bhutkar, Alexander Muir, Tania J. González Robles, Swanny Lamboy Rodríguez, Laura Z. Liao, Sheng Rong Ng, Leanne Li, Caterina I. Colón, Santiago Naranjo, Mary Clare Beytagh, Caroline A. Lewis, Peggy P. Hsu, Roderick T. Bronson, Matthew G. Vander Heiden, and Tyler Jacks. Keap1 mutation renders lung adenocarcinomas dependent on slc33a1. Jun 2020. URL: https://doi.org/10.1038/s43018-020-0071-1, doi:10.1038/s43018-020-0071-1. This article has 75 citations and is from a highest quality peer-reviewed journal.
(chung2024spc2modulatessubstrate pages 3-4): Yeonji Chung, Chewon Yim, Gilberto P. Pereira, Sungjoon Son, Lisbeth R. Kjølbye, Lauren E. Mazurkiewicz, Amy M. Weeks, Friedrich Förster, Gunnar von Heijne, Paulo C.T. Souza, and Hyun Kim. Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex. Journal of Cell Biology, Nov 2024. URL: https://doi.org/10.1083/jcb.202211035, doi:10.1083/jcb.202211035. This article has 4 citations and is from a highest quality peer-reviewed journal.
(chen2021comprehensiveanalysisof pages 39-40): Zhen Chen, Chao Wang, Xu Feng, Litong Nie, Mengfan Tang, Huimin Zhang, Yun Xiong, Samuel K. Swisher, Mrinal Srivastava, and Junjie Chen. Comprehensive analysis of the host-virus interactome of sars-cov-2. bioRxiv, Jan 2021. URL: https://doi.org/10.1101/2020.12.31.424961, doi:10.1101/2020.12.31.424961. This article has 19 citations.
(matthaei2024landscapeofproteinprotein pages 1-2): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
(matthaei2024landscapeofproteinprotein pages 11-14): Alina Matthaei, Sebastian Joecks, Annika Frauenstein, Janina Bruening, Dorothea Bankwitz, Martina Friesland, Gisa Gerold, Gabrielle Vieyres, Lars Kaderali, Felix Meissner, and Thomas Pietschmann. Landscape of protein-protein interactions during hepatitis c virus assembly and release. Feb 2024. URL: https://doi.org/10.1128/spectrum.02562-22, doi:10.1128/spectrum.02562-22. This article has 9 citations and is from a domain leading peer-reviewed journal.
UniProt: Q15005 (SPCS2_HUMAN), 226 aa; aka SPC25, "Microsomal signal peptidase 25 kDa subunit". HGNC:28962, chr 11. Multi-pass ER membrane protein (two TM helices ~87-107 and 112-132), N and C termini cytosolic.
Non-catalytic accessory subunit of the ER signal peptidase complex; ER multi-pass membrane protein that enhances SPC enzymatic activity and facilitates interactions at the translocation site, contributing to signal peptide processing of preproteins.
ER proteostasis|Protein transport|ER signal peptidase; PN-node mapping: group mapped, ok_for_propagation_to_go, GO:0005787 (signal peptidase complex); class GO:0015031 (protein transport).This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q15005
gene_symbol: SPCS2
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: SPCS2 (signal peptidase complex subunit 2, also SPC25, the microsomal signal peptidase 25 kDa subunit) is a 226 aa multi-pass endoplasmic reticulum membrane protein that is one of the three non-catalytic accessory subunits (with SPCS1 and SPCS3) of the eukaryotic ER signal peptidase complex (SPC). The SPC removes N-terminal signal sequences from secretory and membrane preproteins as they are translocated into the ER lumen; catalysis resides in the SEC11A or SEC11C subunits. SPCS2 spans the ER membrane twice with both termini facing the cytosol and is thought to enhance the enzymatic activity of the complex and to facilitate interactions between components of the translocation site. Together with the other subunits it helps form the transmembrane window that locally thins the ER bilayer, contributing to the complex's selectivity for signal-peptide hydrophobic regions shorter than about 18-20 residues.
existing_annotations:
- term:
id: GO:0005787
label: signal peptidase complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: SPCS2 is a constitutive accessory subunit of the ER signal peptidase complex; the phylogenetic assignment reflects its core identity.
action: ACCEPT
reason: Core complex membership, supported experimentally by cryo-EM and ComplexPortal curation.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3'
- term:
id: GO:0045047
label: protein targeting to ER
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: SPCS2 does not target proteins to the ER; as part of the signal peptidase complex it acts on already-translocating substrates to cleave the signal peptide. The phylogenetic term is mis-specified; the accurate process is signal peptide processing.
action: MODIFY
reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465).
proposed_replacement_terms:
- id: GO:0006465
label: signal peptide processing
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum
- term:
id: GO:0005787
label: signal peptidase complex
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: part_of
review:
summary: InterPro-based electronic assignment to the signal peptidase complex, consistent with experimental evidence.
action: ACCEPT
reason: Correct core complex membership; redundant with experimental IPI/IBA evidence.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3'
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: SPCS2 is a multi-pass ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization.
action: ACCEPT
reason: Core localization, supported by structure (PMID:34388369) and ortholog topology.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: located_in
review:
summary: Generic membrane localization, a parent of the more informative ER membrane term.
action: KEEP_AS_NON_CORE
reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SPCS2 localization.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: Multi-pass membrane protein
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34232536
qualifier: enables
review:
summary: High-throughput coronavirus interactome capturing an interaction between SPCS2 and the SARS-CoV-2 spike protein; the bare protein binding term is uninformative.
action: KEEP_AS_NON_CORE
reason: High-throughput host-pathogen interaction; bare protein binding is uninformative and not the core function.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'Q15005; P0DTC2: S; Xeno'
- term:
id: GO:0005787
label: signal peptidase complex
evidence_type: IPI
original_reference_id: PMID:34388369
qualifier: part_of
review:
summary: ComplexPortal annotation of SPCS2 as a component of the signal peptidase complex, based on the cryo-EM structure of the human SPC.
action: ACCEPT
reason: Definitive experimental (structural) evidence for SPC membership; the core identity of SPCS2.
supported_by:
- reference_id: PMID:34388369
supporting_text: the human SPC exists in two functional paralogs with distinct proteolytic subunits
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: IDA
original_reference_id: PMID:34388369
qualifier: located_in
review:
summary: Direct (structural) evidence places SPCS2 in the ER membrane as part of the SPC; correct core localization.
action: ACCEPT
reason: IDA-supported ER membrane localization consistent with the membrane-embedded SPC structure.
supported_by:
- reference_id: PMID:34388369
supporting_text: a transmembrane window collectively formed by all subunits locally thins the bilayer
- term:
id: GO:0016485
label: protein processing
evidence_type: IDA
original_reference_id: PMID:34388369
qualifier: involved_in
review:
summary: SPCS2 participates in proteolytic processing of preproteins as part of the signal peptidase complex; the more precise term is signal peptide processing (GO:0006465).
action: ACCEPT
reason: Correct involvement in the SPC's proteolytic processing of substrates; supported by the structural study and ComplexPortal curation. The core process is signal peptide processing.
supported_by:
- reference_id: PMID:34388369
supporting_text: the determinants for signal peptide cleavage
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: located_in
review:
summary: Sequence-similarity transfer of ER membrane localization from an ortholog; consistent with stronger experimental evidence.
action: ACCEPT
reason: Correct core localization, redundant with IDA/IEA evidence.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34388369
qualifier: enables
review:
summary: Interactions with the other SPC subunits (SEC11A/SEC11C, SPCS1, SPCS3) captured during the structural study; bare protein binding is uninformative although the intra-complex interactions are genuine.
action: KEEP_AS_NON_CORE
reason: Real intra-complex interactions but bare protein binding is uninformative; the SPC membership is already captured by GO:0005787.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: Within the complex, interacts with SEC11A or SEC11C and SPCS1
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-422051
qualifier: located_in
review:
summary: Reactome curation of SPCS2 ER membrane localization (preproghrelin signal peptide cleavage context).
action: ACCEPT
reason: Correct core localization; redundant with experimental evidence.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9918795
qualifier: located_in
review:
summary: Reactome curation of SPCS2 ER membrane localization (flavivirus signalase cleavage context).
action: ACCEPT
reason: Correct core localization; redundant with experimental evidence.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
id: GO:0005789
label: endoplasmic reticulum membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9918871
qualifier: located_in
review:
summary: Reactome curation of SPCS2 ER membrane localization (signalase cleavage context).
action: ACCEPT
reason: Correct core localization; redundant with experimental evidence.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
findings: []
- id: PMID:34232536
title: Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.
findings:
- statement: High-throughput affinity-purification interactome of SARS-CoV-2 and human coronavirus proteins; source of the IntAct SPCS2-spike (S) interaction.
reference_section_type: ABSTRACT
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: High-throughput coronavirus interactome; the SPCS2-spike interaction is the source of the bare protein binding annotation and is not relevant to SPCS2's core function.
- id: PMID:34388369
title: Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage.
findings:
- statement: Cryo-EM structures of the two human SPC paralogs identify SPCS2 as an accessory subunit; the complex forms a transmembrane window that locally thins the ER bilayer, generating specificity for signal-peptide hydrophobic-segment length.
reference_section_type: ABSTRACT
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Definitive structural study establishing SPCS2 as an accessory SPC subunit; basis for ComplexPortal annotations.
- id: PMID:39565596
title: Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex.
findings:
- statement: In yeast, depletion or mutation of Spc2 (ortholog of human SPCS2) compromises the SPC's ability to discriminate between substrates and to identify the correct cleavage site; molecular dynamics simulations show that membrane thinning at the center of the SPC is reduced without Spc2, providing a molecular explanation for the altered substrate-recognition properties.
reference_section_type: ABSTRACT
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified (PMID:39565596, doi:10.1083/jcb.202211035). Direct mechanistic evidence (in yeast Spc2, explicitly cross-referenced to human SPCS2) that the SPCS2 accessory subunit contributes to substrate and cleavage-site selection via membrane thinning, beyond the generic "enhances enzymatic activity" UniProt statement. Not in publications cache, so no verbatim supporting_text added.
- id: PMID:36789796
title: Cleavage of the Jaw1 C-terminal region enhances its augmentative effect on the Ca2+ release via IP3 receptors.
findings:
- statement: The C-terminal region of the tail-anchored ER protein Jaw1 (IRAG2/LRMP) is cleaved after insertion specifically by the SEC11A-containing (but not SEC11C-containing) signal peptidase complex; this noncanonical post-insertional cleavage enhances Jaw1's augmentative effect on IP3 receptor-mediated Ca2+ release, linking SPC (of which SPCS2 is an accessory subunit) to ER Ca2+ signaling.
reference_section_type: ABSTRACT
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified (PMID:36789796, doi:10.1242/jcs.260439). Demonstrates a noncanonical SPC substrate (Jaw1) with SEC11A-paralog selectivity; SPCS2 is an accessory subunit of the executing complex but no SPCS2-specific role is assigned. Contextual for the expanded SPC substrate range. Not in publications cache, so no verbatim supporting_text added.
- id: PMID:38230952
title: Landscape of protein-protein interactions during hepatitis C virus assembly and release.
findings:
- statement: An affinity-purification mass-spectrometry interactome of HCV-infected cells found that cell-derived SPCS2 interacts with both HCV p7 and E2, implicating the SPCS2-containing SPC in HCV glycoprotein/viroporin processing at the assembly stage.
reference_section_type: ABSTRACT
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: PubMed-verified (PMID:38230952, doi:10.1128/spectrum.02562-22). High-throughput AP-MS interactome; SPCS2 among host factors binding HCV p7 and E2. Secondary host-pathogen context, not core function. Not in publications cache, so no verbatim supporting_text added.
- id: Reactome:R-HSA-422051
title: Cleavage of the signal peptide of Preproghrelin
findings: []
- id: Reactome:R-HSA-9918795
title: Signalase cleaves prM-E-NS1-NS2A
findings: []
- id: Reactome:R-HSA-9918871
title: Signalase cleaves prepro-NS4B
findings: []
- id: file:human/SPCS2/SPCS2-uniprot.txt
title: UniProt entry Q15005 (SPCS2_HUMAN), signal peptidase complex subunit 2
findings:
- statement: Non-catalytic accessory subunit of the ER signal peptidase complex (SPC-A with SEC11A and SPC-C with SEC11C, each also containing SPCS1 and SPCS3); multi-pass ER membrane protein; enhances SPC enzymatic activity and facilitates translocation-site component interactions.
reference_section_type: OTHER
core_functions:
- description: Non-catalytic accessory subunit of the ER signal peptidase complex that enhances the complex's enzymatic activity and facilitates interactions among translocation-site components, contributing to signal peptide processing of secretory and membrane preproteins.
supported_by:
- reference_id: file:human/SPCS2/SPCS2-uniprot.txt
supporting_text: Enhances the enzymatic activity of SPC and facilitates the interactions between different components of the translocation site
- reference_id: PMID:34388369
supporting_text: a transmembrane window collectively formed by all subunits locally thins the bilayer
molecular_function:
id: GO:0005198
label: structural molecule activity
contributes_to_molecular_function:
id: GO:0009003
label: signal peptidase activity
in_complex:
id: GO:0005787
label: signal peptidase complex
locations:
- id: GO:0005789
label: endoplasmic reticulum membrane
proposed_new_terms: []
suggested_questions:
- question: How does SPCS2 enhance the enzymatic activity of the signal peptidase complex - through stabilization of the catalytic SEC11 subunit, substrate gating, or coupling to the Sec61 translocon?
- question: Is SPCS2 strictly required for SPC assembly and signal-peptide cleavage in human cells, or is it conditionally dispensable like SPCS1?
suggested_experiments:
- description: Compare cleavage kinetics of reconstituted SPC with and without SPCS2 to quantify its proposed activity-enhancing role and substrate-length dependence.
- description: Acute SPCS2 depletion followed by quantitative N-terminomics and translocon proximity proteomics to test whether SPCS2 organizes translocation-site interactions in cells.