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 | REMOVE | 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 cleavage, i.e. protein processing, which this gene already carries as an ACCEPTed IDA annotation (GO:0016485, PMID:34388369). Reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465). GO has since obsoleted GO:0006465 because it represents the molecular function signal peptidase activity (GO:0009003, captured in core_functions); its live process-level parent is protein processing (GO:0016485), which is already an ACCEPTed IDA annotation on this gene (PMID:34388369). A MODIFY to GO:0016485 would duplicate that row, so the mis-specified IBA term is removed rather than replaced. 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; more specifically, the SPC cleaves N-terminal signal peptides (the former GO:0006465 signal peptide processing, now obsolete in GO, for which protein processing is the live process term). 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 cleavage, which GO now represents with this protein processing term (GO:0016485) after obsoleting GO:0006465 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 |
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Download this section (compressed HTML)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.
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