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.