id: Q9BY50
gene_symbol: SEC11C
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SEC11C (SPC21, SEC11L3; EC 3.4.21.89) is a single-pass type II endoplasmic reticulum membrane protein and one of the two catalytic serine-endopeptidase subunits of the human signal peptidase complex (SPC). As the proteolytic subunit of the SPC-C paralog (with accessory subunits SPCS1, SPCS2 and SPCS3), SEC11C catalyzes cleavage of N-terminal signal (leader) peptides from secretory and membrane pre-proteins as they are translocated into the ER lumen. It belongs to peptidase family S26B and uses a Ser/His/Asp-type charge-relay catalytic system (Ser-68 nucleophile). Its active site abuts the ER membrane, where the complex locally thins the lipid bilayer, conferring selectivity for signal peptides whose hydrophobic h-region is shorter than ~18-20 residues. SEC11C is the paralog of the more broadly expressed SEC11A; the two catalytic subunits form distinct but functionally analogous SPC paralogs.
existing_annotations:
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SEC11C is the catalytic subunit of the signal peptidase complex (SPC-C paralog); membership in the SPC is its defining, conserved cellular component.
    action: ACCEPT
    reason: Core cellular component; SEC11C is the proteolytic subunit of the signal peptidase complex.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog C (SPC-C)
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: SEC11C is a peptidase; "peptidase activity" is a correct but generic parent of the specific serine-type endopeptidase/signal peptidase activity.
    action: ACCEPT
    reason: Correct general molecular function; the specific serine-type endopeptidase activity (GO:0004252) better captures SEC11C's catalytic role.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Belongs to the peptidase S26B family
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: SEC11C is a serine-type endopeptidase that uses a Ser/His/Asp charge-relay catalytic triad to cleave signal peptides; this is its core molecular function.
    action: ACCEPT
    reason: Core molecular function; experimentally established serine-endopeptidase (signal peptidase) activity, supported by IDA/EXP and the catalytic triad.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: The active site is formed by a
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: ARBA electronic assignment of signal peptidase complex membership, redundant with the experimental IDA evidence.
    action: ACCEPT
    reason: Correct core cellular component; redundant with IDA/IBA evidence.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog C (SPC-C)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic assignment of ER membrane localization from the UniProt subcellular location, consistent with the single-pass type II ER membrane topology.
    action: ACCEPT
    reason: Correct core localization; SEC11C is a single-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0008233
    label: peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of peptidase activity; a generic parent of the specific serine-type endopeptidase activity.
    action: ACCEPT
    reason: Correct general molecular function; GO:0004252 is the informative specific term.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Belongs to the peptidase S26B family
- term:
    id: GO:0009003
    label: signal peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: EC-based electronic assignment of signal peptidase activity (EC 3.4.21.89); this is SEC11C's specific catalytic function and is experimentally supported (EXP).
    action: ACCEPT
    reason: Core molecular function; SEC11C is the catalytic signal peptidase of the SPC-C complex (EC 3.4.21.89).
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: EC=3.4.21.89
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: SEC11C is a membrane protein; "membrane" is a correct but generic parent of the specific ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; ER membrane (GO:0005789) is the specific and informative localization.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: BioPlex (HCIP) high-throughput interactome capture; bare protein binding is uninformative for core function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; uninformative bare term not elevated to core per guidelines.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'Q9BY50; P61009: SPCS3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome (HuRI) high-throughput capture; bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; uninformative bare term not elevated to core.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'Q9BY50; P61009: SPCS3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex proteome-scale interactome capture; bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; uninformative bare term not elevated to core.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'Q9BY50; P61009: SPCS3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: enables
  review:
    summary: SEC11C interacts with the SPC accessory subunits SPCS2 and SPCS3 within the signal peptidase complex; the bare protein binding term is uninformative, but the SPC assembly is captured better by the signal peptidase complex part_of annotation.
    action: KEEP_AS_NON_CORE
    reason: Records genuine intra-complex interactions (SPCS2/SPCS3), but bare protein binding is uninformative; the functional content is captured by the signal peptidase complex CC.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: with SPCS2 and SPCS3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map (proteomics/imaging) high-throughput capture; bare protein binding is uninformative for core function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome/cell-map interaction; uninformative bare term not elevated to core.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'Q9BY50; P61009: SPCS3'
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: part_of
  review:
    summary: The cryo-EM structure identifies SEC11C within the assembled signal peptidase complex (SPC-C) with SPCS1/2/3; defining cellular component.
    action: ACCEPT
    reason: Core cellular component; SEC11C is the catalytic subunit of the structurally resolved SPC-C complex.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog C (SPC-C)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: located_in
  review:
    summary: The SPC structure places SEC11C in the ER membrane, with the active site abutting the bilayer; direct experimental localization.
    action: ACCEPT
    reason: Core localization with direct experimental support; SEC11C acts at the ER membrane.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: involved_in
  review:
    summary: SEC11C processes pre-proteins by cleaving their signal peptides; "protein processing" is a correct but generic parent of the specific signal peptide processing.
    action: ACCEPT
    reason: Correct biological process; the specific signal peptide processing (GO:0006465) better captures SEC11C's role.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: it removes signal peptides (SPs) from a large
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity (ISS) transfer of ER membrane localization, consistent with the experimental IDA evidence.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA/IEA ER membrane evidence.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0009003
    label: signal peptidase activity
  evidence_type: EXP
  original_reference_id: PMID:34388369
  qualifier: enables
  review:
    summary: Experimental demonstration (structure + catalytic-activity/mutagenesis of the catalytic triad including Ser-68) that SEC11C is a catalytic signal peptidase of the SPC. This is the core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; SEC11C is a catalytic signal peptidase subunit of the SPC.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: human SPC exists in two functional paralogs with distinct proteolytic
        subunits
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: enables
  review:
    summary: Direct experimental demonstration of SEC11C serine-type endopeptidase (signal peptidase) activity via the resolved catalytic triad and catalytic-activity assays; core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental (IDA) support.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: The active site is formed by a
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: part_of
  review:
    summary: Direct structural demonstration that SEC11C is the catalytic subunit within the assembled SPC-C; defining cellular component.
    action: ACCEPT
    reason: Core cellular component with direct experimental (IDA) support.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog C (SPC-C)
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: involved_in
  review:
    summary: By cleaving signal peptides from pre-proteins, SEC11C contributes to maturation of secretory/membrane proteins; "protein maturation" is a correct but generic parent of the specific signal peptide processing.
    action: ACCEPT
    reason: Correct biological process; the specific signal peptide processing (GO:0006465) better captures SEC11C's role.
    supported_by:
    - reference_id: PMID:34388369
      supporting_text: it removes signal peptides (SPs) from a large
- 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 SEC11C ER membrane localization (preproghrelin signal peptide cleavage).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-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 SEC11C ER membrane localization (flaviviral polyprotein signalase cleavage).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-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 SEC11C ER membrane localization (NS4B signalase cleavage).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/SEC11C/SEC11C-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:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  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, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex (HCIP) interactome; source of a generic protein-binding IPI annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary (HuRI/Y2H) interactome; source of a generic protein-binding IPI annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale interactome; source of a generic protein-binding IPI annotation.
- id: PMID:34388369
  title: Structure of the human signal peptidase complex reveals the determinants
    for signal peptide cleavage.
  findings:
  - statement: The human signal peptidase complex exists in two functional paralogs with distinct proteolytic subunits (SEC11A and SEC11C); the active site is formed by a catalytic triad abutting the ER membrane, where a transmembrane window thins the bilayer to generate specificity for signal peptides based on the length of their hydrophobic segments.
    reference_section_type: ABSTRACT
  - statement: SEC11C is the catalytic subunit of SPC-C (with accessory subunits SPCS1, SPCS2, SPCS3); Ser-68 is the catalytic nucleophile and the C-terminal short (CTS) helix is essential for catalytic activity.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural/mechanistic study establishing SEC11C as a catalytic SPC paralog subunit, its catalytic triad, EC 3.4.21.89, and the membrane-thinning specificity mechanism.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map (proteomics/imaging) study; source of a generic protein-binding IPI annotation.
- id: PMID:36454823
  title: The human signal peptidase complex acts as a quality control enzyme for membrane
    proteins.
  findings:
  - statement: Beyond canonical N-terminal signal peptide removal, the human SPC (catalytic
      core SEC11A/C with SPCS3) cleaves misfolded or unassembled membrane proteins
      at otherwise hidden "cryptic" cleavage sites abundant in the human membrane proteome;
      this post-translocational cleavage synergizes with ER-associated degradation
      (ERAD) to maintain membrane protein homeostasis. SEC11A knockdown did not abolish
      a noncanonical cleavage event, consistent with compensation by SEC11C.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1126/science.abo5672, Science 2022). Establishes
      a membrane-protein quality-control function of the SPC catalytic core (SEC11A/C)
      and implicates SEC11C as a redundant/backup catalytic subunit when SEC11A is
      limiting. Not in GOA; informs BP context but no new SEC11C-specific GO annotation
      added.
- id: PMID:28423309
  title: The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue
    Virus Replication by Inhibition of the Host Signal Peptidase.
  findings:
  - statement: Genome-wide CRISPR/Cas9 chemogenomic profiling in human cells and resistance
      selection in yeast identified the catalytic subunit of the signal peptidase
      (SEC11; human SEC11A and SEC11C) as the conserved efficacy target of cavinafungin,
      which rapidly blocks signal-sequence cleavage of host and viral proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1016/j.celrep.2017.03.071, Cell Rep 2017).
      Identifies human SEC11A/SEC11C as the conserved drug target; supports SEC11C's
      essential signal peptidase activity and chemical-biology/antiviral relevance.
- id: PMID:39565596
  title: Spc2 modulates substrate- and cleavage site-selection in the yeast signal
    peptidase complex.
  findings:
  - statement: In yeast, the noncatalytic SPC subunit Spc2 (ortholog of human SPCS2)
      modulates SPC discrimination between substrates and cleavage-site selection;
      molecular dynamics indicates Spc2 contributes to the membrane thinning at the
      center of the SPC that underlies substrate recognition, informing the conserved
      mechanism by which accessory subunits support the SEC11 catalytic subunit.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1083/jcb.202211035, J Cell Biol 2024). Yeast
      study; mechanistically relevant to human SEC11C by clarifying how noncatalytic
      subunits shape substrate/cleavage-site selection of the SEC11 protease.
- id: PMID:26446786
  title: Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable
    Mutant Preprotein Cargos.
  findings:
  - statement: A non-cleavable variant preprotein (proline introduced immediately after
      the signal-peptide cleavage site) is translocated across the ER membrane where
      it binds the catalytic SPase subunit and inhibits signal peptidase activity in
      a dose-dependent manner; this work directly implicates SEC11A as the catalytic
      subunit and establishes eukaryotic SPase as a tractable antiviral target, informing
      the shared catalytic mechanism of the SEC11A/SEC11C signal peptidase paralogs.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:26446786, DOI 10.1074/jbc.M115.692350, J Biol
      Chem 2015). Abstract names SEC11A (not SEC11C) as the bound catalytic subunit;
      relevant to SEC11C only as background for the conserved eukaryotic SPase catalytic
      mechanism and druggability. Not in GOA; no new core GO annotation 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/SEC11C/SEC11C-uniprot.txt
  title: UniProt entry Q9BY50 (SC11C_HUMAN), Signal peptidase complex catalytic subunit
    SEC11C
  findings:
  - statement: SEC11C is the catalytic subunit of the signal peptidase complex paralog C (SPC-C) with SPCS1/2/3; cleaves N-terminal signal peptides (EC 3.4.21.89) from nascent proteins translocated into the ER lumen; single-pass type II ER membrane protein; peptidase S26B family; catalytic triad (Ser-68), selectivity for h-regions shorter than 18-20 residues via membrane thinning.
    reference_section_type: OTHER
core_functions:
- description: Catalytic serine-endopeptidase subunit of the ER signal peptidase complex (SPC-C paralog) that cleaves N-terminal signal peptides from secretory and membrane pre-proteins as they are translocated into the ER lumen, using a Ser/His/Asp catalytic triad.
  molecular_function:
    id: GO:0004252
    label: serine-type endopeptidase activity
  in_complex:
    id: GO:0005787
    label: signal peptidase complex
  supported_by:
  - reference_id: file:human/SEC11C/SEC11C-uniprot.txt
    supporting_text: catalyzes the cleavage of N-terminal signal sequences
  - reference_id: PMID:34388369
    supporting_text: The active site is formed by a
  directly_involved_in:
  - id: GO:0016485
    label: protein processing
proposed_new_terms: []
suggested_questions:
- question: What distinguishes the substrate specificity of the SEC11C (SPC-C) versus SEC11A (SPC-A) paralogous signal peptidase complexes, and do they serve distinct subsets of the secretory proteome or distinct tissues?
- question: How does the SPC's local thinning of the ER membrane mechanistically couple signal-peptide h-region length to catalytic engagement by SEC11C?
suggested_experiments:
- description: Reconstitute purified SPC-C (SEC11C + SPCS1/2/3) and assay cleavage of a panel of signal peptides varying in h-region length to quantify SEC11C's length-dependent specificity, comparing wild-type Ser-68 to the catalytic-dead S68A mutant.
- description: Acute degron depletion of SEC11C versus SEC11A followed by N-terminomics (e.g. TAILS) to define the paralog-specific repertoire of cleaved signal-peptide substrates in human cells.