SEC11A (SPC18, SEC11L1; 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-A paralog (with accessory subunits SPCS1, SPCS2 and SPCS3), SEC11A 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-56 nucleophile). Its active site abuts the ER membrane, where the complex locally thins the lipid bilayer; this architecture confers selectivity for signal peptides whose hydrophobic h-region is shorter than ~18-20 residues. SEC11A is the more broadly/highly expressed of the two catalytic paralogs (the other being SEC11C) and is broadly required for biogenesis of the secretory proteome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005787 signal peptidase complex | IBA GO_REF:0000033 | ACCEPT | Summary: SEC11A is the catalytic subunit of the signal peptidase complex (SPC-A paralog); membership in the SPC is its defining, conserved cellular component. Reason: Core cellular component; SEC11A is the proteolytic subunit of the signal peptidase complex. Supporting Evidence: file:human/SEC11A/SEC11A-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:0008233 peptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: SEC11A is a peptidase; "peptidase activity" is a correct but generic parent of the specific serine-type endopeptidase/signal peptidase activity. Reason: Correct general molecular function; the specific serine-type endopeptidase activity (GO:0004252) better captures SEC11A's catalytic role. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Belongs to the peptidase S26B family |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: SEC11A 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. Reason: Core molecular function; experimentally established serine-endopeptidase (signal peptidase) activity, supported by IDA/EXP and the catalytic triad. Supporting Evidence: PMID:34388369 The active site is formed by a |
| GO:0005787 signal peptidase complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic assignment of signal peptidase complex membership, redundant with the experimental IDA evidence. Reason: Correct core cellular component; redundant with IDA/IBA evidence. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of ER membrane localization from the UniProt subcellular location, consistent with the single-pass type II ER membrane topology. Reason: Correct core localization; SEC11A is a single-pass ER membrane protein. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0008233 peptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of peptidase activity; a generic parent of the specific serine-type endopeptidase activity. Reason: Correct general molecular function; GO:0004252 is the informative specific term. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Belongs to the peptidase S26B family |
| GO:0009003 signal peptidase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-based electronic assignment of signal peptidase activity (EC 3.4.21.89); this is SEC11A's specific catalytic function and is experimentally supported (EXP). Reason: Core molecular function; SEC11A is the catalytic signal peptidase of the SPC (EC 3.4.21.89). Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt EC=3.4.21.89 |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: SEC11A is a membrane protein; "membrane" is a correct but generic parent of the specific ER membrane localization. Reason: Correct but generic; ER membrane (GO:0005789) is the specific and informative localization. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Single-pass type II membrane protein |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome (HuRI) high-throughput capture; bare protein binding is uninformative for core function. Reason: High-throughput interactome interaction; uninformative bare term not elevated to core per guidelines. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt P67812; P61009: SPCS3 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex proteome-scale interactome capture; bare protein binding is uninformative. Reason: High-throughput interactome interaction; uninformative bare term not elevated to core. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt P67812; P61009: SPCS3 |
| GO:0005515 protein binding | IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ... | KEEP AS NON CORE | Summary: SEC11A 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. 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. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt with SPCS2 and SPCS3 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map (proteomics/imaging) high-throughput capture; bare protein binding is uninformative for core function. Reason: High-throughput interactome/cell-map interaction; uninformative bare term not elevated to core. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt P67812; P61009: SPCS3 |
| GO:0004252 serine-type endopeptidase activity | TAS Reactome:R-HSA-9829030 | ACCEPT | Summary: Reactome curation of SEC11A serine-endopeptidase activity (cleavage of a viral fusion-protein signal peptide at the ER membrane); consistent with its core catalytic function. Reason: Correct core molecular function; redundant with experimental signal peptidase activity. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt catalyzes the cleavage of N-terminal signal sequences |
| GO:0004252 serine-type endopeptidase activity | TAS Reactome:R-HSA-9932162 | ACCEPT | Summary: Reactome curation of SEC11A serine-endopeptidase activity (removal of the CDH1 signal peptide); consistent with its core catalytic function. Reason: Correct core molecular function; redundant with experimental signal peptidase activity. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt catalyzes the cleavage of N-terminal signal sequences |
| GO:0005787 signal peptidase complex | IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: The cryo-EM structure identifies SEC11A within the assembled signal peptidase complex (SPC-A) with SPCS1/2/3; defining cellular component. Reason: Core cellular component; SEC11A is the catalytic subunit of the structurally resolved SPC-A complex. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: The SPC structure places SEC11A in the ER membrane, with the active site abutting the bilayer; direct experimental localization. Reason: Core localization with direct experimental support; SEC11A acts at the ER membrane. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt nascent proteins as they are translocated into the lumen of the endoplasmic reticulum |
| GO:0016485 protein processing | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: SEC11A processes pre-proteins by cleaving their signal peptides; "protein processing" is a correct but generic parent of the specific signal peptide processing. Reason: Correct biological process; the specific GO:0006465 (signal peptide processing) better captures SEC11A's role. Supporting Evidence: PMID:34388369 it removes signal peptides (SPs) from a large |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of ER membrane localization, consistent with the experimental IDA evidence. Reason: Correct core localization; redundant with IDA/IEA ER membrane evidence. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0009003 signal peptidase activity | EXP PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: Experimental demonstration (structure + catalytic-activity/mutagenesis of the catalytic triad including Ser-56) that SEC11A is the catalytic signal peptidase of the SPC. This is the core molecular function. Reason: Core molecular function with direct experimental support; SEC11A is the catalytic signal peptidase subunit of the SPC. Supporting Evidence: PMID:34388369 human SPC exists in two functional paralogs with distinct proteolytic subunits |
| GO:0009615 response to virus | TAS Reactome:R-HSA-9820965 | MARK AS OVER ANNOTATED | Summary: Reactome annotation arising because SEC11A signal peptidase processes viral (e.g. RSV) polyprotein signal peptides during the viral life cycle. This is a downstream consequence of its general signal peptidase activity on viral substrates, not a dedicated antiviral/host-response function. Reason: SEC11A's involvement reflects generic signal peptidase processing of viral substrates within Reactome viral pathways; "response to virus" over-extends this to a dedicated antiviral biological process the protein does not have. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt catalyzes the cleavage of N-terminal signal sequences |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: Direct experimental demonstration of SEC11A serine-type endopeptidase (signal peptidase) activity via the resolved catalytic triad and catalytic-activity assays; core molecular function. Reason: Core molecular function with direct experimental (IDA) support. Supporting Evidence: PMID:34388369 The active site is formed by a |
| GO:0005787 signal peptidase complex | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: Direct structural demonstration that SEC11A is the catalytic subunit within the assembled SPC-A; defining cellular component. Reason: Core cellular component with direct experimental (IDA) support. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) |
| GO:0051604 protein maturation | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: By cleaving signal peptides from pre-proteins, SEC11A contributes to maturation of secretory/membrane proteins; "protein maturation" is a correct but generic parent of the specific signal peptide processing. Reason: Correct biological process; the specific GO:0006465 (signal peptide processing) better captures SEC11A's role. Supporting Evidence: PMID:34388369 it removes signal peptides (SPs) from a large |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-422051 | ACCEPT | Summary: Reactome curation of SEC11A ER membrane localization (preproghrelin signal peptide cleavage). Reason: Correct core localization; redundant with experimental ER membrane evidence. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9918795 | ACCEPT | Summary: Reactome curation of SEC11A ER membrane localization (flaviviral polyprotein signalase cleavage). Reason: Correct core localization; redundant with experimental ER membrane evidence. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9918871 | ACCEPT | Summary: Reactome curation of SEC11A ER membrane localization (NS4B signalase cleavage). Reason: Correct core localization; redundant with experimental ER membrane evidence. Supporting Evidence: file:human/SEC11A/SEC11A-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
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Download this section (compressed HTML)Q: What distinguishes the substrate specificity of the SEC11A (SPC-A) versus SEC11C (SPC-C) paralogous signal peptidase complexes in human cells, and do they serve distinct subsets of the secretory proteome?
Q: How does the SPC's local thinning of the ER membrane mechanistically couple signal-peptide h-region length to catalytic engagement by SEC11A?
Experiment: Reconstitute purified SPC-A (SEC11A + SPCS1/2/3) and assay cleavage of a panel of signal peptides varying in h-region length to quantify SEC11A's length-dependent specificity, comparing wild-type Ser-56 to the S56A catalytic-dead mutant.
Experiment: Acute degron depletion of SEC11A versus SEC11C followed by N-terminomics (e.g. TAILS) to define the paralog-specific repertoire of cleaved signal-peptide substrates in human cells.
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