Existing Annotations Review

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

Core Functions

Catalytic serine-endopeptidase subunit of the ER signal peptidase complex (SPC-A 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:

serine-type endopeptidase activity

Directly Involved In:

protein processing

In Complex:

signal peptidase complex

Supporting Evidence:

file:human/SEC11A/SEC11A-uniprot.txt
catalyzes the cleavage of N-terminal signal sequences
PMID:34388369
The active site is formed by a

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34388369

Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage.

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.
SEC11A is the catalytic subunit of SPC-A (with accessory subunits SPCS1, SPCS2, SPCS3); Ser-56 is the catalytic nucleophile and the C-terminal short (CTS) helix is essential for catalytic activity.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:36454823

The human signal peptidase complex acts as a quality control enzyme for membrane proteins.

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, which are abundant in the human membrane proteome; this post-translocational cleavage synergizes with ER-associated degradation (ERAD) to maintain membrane protein homeostasis.

PMID:28423309

The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase.

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.

PMID:39565596

Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex.

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.

PMID:26446786

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos.

A non-cleavable variant preprotein (proline introduced immediately after the signal-peptide cleavage site, e.g. preproinsulin pPI-F25P) is translocated across the ER membrane where it binds the catalytic SPase subunit SEC11A and inhibits signal peptidase activity in a dose-dependent manner, impairing in trans the processing/maturation of co-expressed preproteins and of viral polypeptides; this identifies eukaryotic SPase (human SEC11A) as a tractable therapeutic/antiviral target.

PMID:36456166

Clinical Significance of SEC11A Expression in Patients With Locally Advanced Gastric Cancer.

In locally advanced gastric cancer (n=253), high SEC11A mRNA expression was associated with worse 5-year overall survival and was an independent predictor of poor prognosis in multivariate analysis.

PMID:35653344

Signal peptidase complex catalytic subunit SEC11A upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma.

In TCGA head and neck squamous cell carcinoma, SEC11A was upregulated in tumors versus adjacent normal tissue and higher SEC11A expression independently predicted poorer progression-free and disease-specific survival; expression correlated with SEC11A copy number.

Reactome:R-HSA-422051

Cleavage of the signal peptide of Preproghrelin

Reactome:R-HSA-9820965

Respiratory syncytial virus (RSV) genome replication, transcription and translation

Reactome:R-HSA-9829030

Nascent F signal peptide is cleaved at ER membrane

Reactome:R-HSA-9918795

Signalase cleaves prM-E-NS1-NS2A

Reactome:R-HSA-9918871

Signalase cleaves prepro-NS4B

Reactome:R-HSA-9932162

Removal of CDH1 signal peptide

file:human/SEC11A/SEC11A-uniprot.txt

UniProt entry P67812 (SC11A_HUMAN), Signal peptidase complex catalytic subunit SEC11A

SEC11A is the catalytic subunit of the signal peptidase complex paralog A (SPC-A) 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-56), selectivity for h-regions shorter than 18-20 residues via membrane thinning.

Suggested Experiments

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.

Deep Research

Falcon

(SEC11A-deep-research-falcon.md)

Comprehensive Research Report: Human **SEC11A** (SPC18) Functional Annotation (UniProt **P67812**) Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-12T02:56:47.211826

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000013 The main cryo-EM structure of the human signal peptidase complex (SPC) and its functional features are primarily detailed in Figure (image/png)

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.

Comprehensive Research Report: Human SEC11A (SPC18) Functional Annotation (UniProt P67812)

1) Target verification (identity, organism, family)

The target gene/protein in this report is human SEC11A (synonyms: SEC11L1, SPC18), corresponding to the proteolytic subunit SEC11A/SPC18 of the endoplasmic reticulum (ER) signal peptidase complex (SPC), consistent with the UniProt-provided description for accession P67812. SEC11A is discussed in the literature as one of two proteolytic SEC11 paralogs (SEC11A and SEC11C) that form distinct human SPC paralogs (SPC-A vs SPC-C). (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4)

2) Key concepts and current understanding

2.1 Signal peptides and their canonical cleavage rules

Secretory and many membrane proteins enter the ER with N-terminal signal peptides (SPs) that are removed by the SPC. Canonical signal peptides have a tripartite architecture: an N-region (often positively charged), a hydrophobic h-region, and a more polar c-region that contains the scissile bond. Cleavage efficiency is strongly influenced by the -1/-3 rule (small, non-charged residues at positions -1 and -3 relative to the cleavage site). (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4, zanotti2023characterisationofthe pages 53-57)

2.2 SEC11A as the catalytic component of the eukaryotic SPC

SEC11A is a membrane-embedded serine protease subunit of the SPC that performs signal peptide cleavage in the ER. Human SPC exists as two functional paralogs with distinct proteolytic subunits: SPC-A (containing SEC11A) and SPC-C (containing SEC11C). Both paralogs share the same accessory subunits. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 7-8)

2.3 Complex composition, architecture, and subunit roles

Cryo-EM/structural proteomics work indicates the human SPC is a heterotetramer comprising SPC12 (SPCS1), SPC25 (SPCS2), SPC22/23 (SPCS3), and one proteolytic SEC11 paralog (SEC11A or SEC11C). (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4)

SEC11A/C and SPC22/23 contribute major luminal structural elements, while the transmembrane (TM) helices of all subunits define a lipid-filled “TM window” near the active site. (liaci2021structureofthe pages 10-12, liaci2021structureofthe pages 3-4)

2.4 Enzymatic mechanism: catalytic triad and reaction

The SPC active site is described as a Ser–His–Asp catalytic triad typical of a serine protease, positioned near the luminal membrane surface to cleave SPs as they emerge into/along the ER membrane interface. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)

2.5 Substrate specificity: “measuring” the signal peptide h-region

A central specificity principle emerging from structural and simulation analyses is that the SPC discriminates SPs from TM helices using membrane shaping: the TM window locally thins the bilayer. This architecture provides specificity for signal peptides with relatively short h-regions (often ~7–15 amino acids) and excludes longer TM helices; experimentally, substrates with h-regions >18–20 aa are generally not cleaved by the eukaryotic SPC. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12, liaci2021structureofthe pages 7-8)

3) Subcellular localization and pathway context

SEC11A functions as part of the SPC at the endoplasmic reticulum membrane, where it cleaves N-terminal signal peptides during secretory-pathway biogenesis. (liaci2021structureofthe pages 1-3, chung2024spc2modulatessubstrate pages 1-2)

4) Recent developments and latest research (emphasis 2023–2024)

4.1 2024: Noncatalytic subunits modulate substrate and cleavage-site selection

A 2024 Journal of Cell Biology study in yeast (highly conserved SPC biology) provides mechanistic insight that noncatalytic subunits can modulate discrimination between substrates and cleavage site selection; it highlights stabilization of the catalytic region of Sec11 (human SEC11A/C orthologs) by the luminal domain of the SPCS3 ortholog as part of the catalytic core. While not a human SEC11A-only study, it informs the conserved mechanism by which the SEC11 protease is supported by other SPC subunits. (chung2024spc2modulatessubstrate pages 1-2)

4.2 2023: SPC as a membrane-protein quality-control enzyme and noncanonical cleavage

A 2023 characterization of the human SPC proposes that, beyond canonical SP removal, the SPC can act in quality control for membrane proteins, including cleavage at cryptic/noncanonical sites in misfolded membrane proteins. This work reports an in silico identification of ~1500 membrane proteins containing putative cryptic SPC cleavage sites and proposes SPCS1 as a recruitment factor (exosite-like function) for noncanonical substrates. (zanotti2023characterisationofthe pages 53-57)

4.3 Structural visualization (supporting evidence)

Cropped figure regions from the SPC cryo-EM study visually show the overall architecture, proximity of the catalytic triad to the membrane, and the TM window/membrane thinning concept that underpins specificity. (liaci2021structureofthe media 1e096f5b, liaci2021structureofthe media e7dabb13, liaci2021structureofthe media 5164c33e)

5) Current applications and real-world implementations

5.1 Biomarker applications in oncology (prognostic associations)

SEC11A expression has been evaluated as a prognostic biomarker in multiple cancers.

Locally advanced gastric cancer (cohort study; qRT-PCR on tumor specimens): In n=253 patients, high SEC11A expression (n=127) vs low (n=126) was associated with worse 5-year overall survival (52.3% vs 75.9%) and remained an independent predictor in multivariate Cox analysis (HR 2.010, 95% CI 1.303–3.100; p=0.002). (Suematsu et al., 2022-12-01; https://doi.org/10.21873/anticanres.16097) (suematsu2022clinicalsignificanceof pages 2-4, suematsu2022clinicalsignificanceof pages 4-5)
Head and neck squamous cell carcinoma (TCGA analysis): In TCGA-HNSC, SEC11A was upregulated in tumors (primary n=518) vs adjacent normal (n=44), and higher SEC11A expression independently predicted poorer outcomes: multivariable PFS HR 2.075 (95% CI 1.447–2.977; p<0.001) and DSS HR 2.023 (95% CI 1.284–3.187; p=0.002). SEC11A expression correlated with SEC11A copy number (r=0.53, p<0.001), consistent with amplification-associated upregulation. (Hu et al., 2022-06-01; https://doi.org/10.1371/journal.pone.0269166) (hu2022signalpeptidasecomplex pages 1-2, hu2022signalpeptidasecomplex pages 2-4)

These studies are examples of real-world implementation as molecular stratification markers (research/retrospective clinical genomics), rather than established clinical diagnostics; they nevertheless provide quantitative effect sizes and suggest SEC11A’s potential utility in risk models. (suematsu2022clinicalsignificanceof pages 2-4, hu2022signalpeptidasecomplex pages 2-4)

5.2 Mechanistic translational relevance: secretion and growth-factor signaling

Clinical biomarker literature contextualizes SEC11A/SPC18 as potentially influencing tumor progression via effects on the secretion of growth factors and downstream signaling (e.g., EGFR pathway activation). While mechanistic steps are not fully proven in the excerpts here, this hypothesis is explicitly discussed as a plausible mediator linking an ER signal-peptide processing enzyme to cancer phenotypes. (suematsu2022clinicalsignificanceof pages 4-5, hu2022signalpeptidasecomplex pages 9-11)

6) Expert opinions and analysis (authoritative interpretation from sources)

6.1 Mechanistic consensus from structural work

Structural evidence supports an “enzyme + membrane-shaping” model: the SPC is not only a protease but also an ER membrane machine that creates a locally thinned bilayer to enforce signal-peptide specificity at scale (thousands of substrates). This provides a coherent physical explanation for how the SPC achieves broad specificity for SPs yet avoids cleaving typical transmembrane helices. (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)

6.2 Emerging view of broader SPC roles

Recent functional work proposes that the SPC participates in quality control by cleaving misfolded membrane proteins at cryptic sites and that accessory subunits may contribute exosite-like recruitment functions. This expands SEC11A’s functional context beyond the classical textbook role of “signal peptide removal,” while remaining consistent with a protease whose active site is positioned to access luminal-proximal segments near the membrane. (zanotti2023characterisationofthe pages 53-57)

7) Relevant statistics and data highlights

Topic	Key finding (with numbers)	Evidence source (first author year)	DOI/URL	Publication date
Functional role in SPC	SEC11A/SPC18 is a catalytic subunit of the human ER-resident signal peptidase complex (SPC) that removes N-terminal signal peptides from secretory pre-proteins; the human SPC is estimated to process ~3,000 human signal peptides (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)	Liaci 2021	https://doi.org/10.2139/ssrn.3778304	2021-01
Complex composition / paralogs	Human SPC exists as 2 heterotetrameric paralogs: SPC-A contains SEC11A and SPC-C contains SEC11C; both also contain SPC12/SPCS1, SPC25/SPCS2, and SPC22/23/SPCS3; reconstituted complex is ~84 kDa (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 7-8)	Liaci 2021	https://doi.org/10.2139/ssrn.3778304	2021-01
Catalytic mechanism / triad	SEC11A/C functions as a serine protease with a catalytic Ser-His-Asp triad; the active site lies adjacent to the ER membrane and is stabilized by SPC22/23/SPCS3; the SPC is resistant to standard serine protease inhibitors (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12, chung2024spc2modulatessubstrate pages 1-2)	Liaci 2021; Chung 2024	https://doi.org/10.2139/ssrn.3778304 ; https://doi.org/10.1083/jcb.202211035	2021-01; 2024-11
Signal peptide determinants / substrate specificity	SPC recognizes canonical signal peptides with a tripartite n/h/c architecture; h-regions are typically 7–15 aa, c-regions 3–7 aa, and efficient cleavage follows the -1/-3 rule requiring small, non-charged residues; eukaryotic SPC generally does not cleave substrates with h-regions >18–20 aa (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 3-4, liaci2021structureofthe pages 7-8, chung2024spc2modulatessubstrate pages 1-2)	Liaci 2021; Chung 2024	https://doi.org/10.2139/ssrn.3778304 ; https://doi.org/10.1083/jcb.202211035	2021-01; 2024-11
Membrane thinning / TM window / lipid dependence	All SPC subunits form a ~15 Å transmembrane window that locally thins the bilayer from ~4 nm to ~2.3–2.6 nm, helping discriminate short signal-peptide h-regions from longer TM helices; phosphatidylcholine enrichment in the window and relipidation can restore activity in detergent systems (liaci2021structureofthe pages 10-12, liaci2021structureofthe media 1e096f5b)	Liaci 2021	https://doi.org/10.2139/ssrn.3778304	2021-01
Quality control / noncanonical cleavage	Beyond canonical signal peptide removal, 2023 work characterized the human SPC as a quality-control enzyme for membrane proteins; ~1,500 membrane proteins were predicted to contain putative cryptic SPC cleavage sites, and SPCS1 was proposed to recruit noncanonical substrates; SEC11A knockdown did not abolish cleavage of at least one noncanonical substrate (Cx32), consistent with compensation by SEC11C (zanotti2023characterisationofthe pages 53-57)	Zanotti 2023	https://doi.org/10.11588/heidok.00033417	2023-01
Clinical association: gastric cancer	In locally advanced gastric cancer, SEC11A mRNA was measured in n=253 patients (high n=127, low n=126). High expression associated with worse 5-year overall survival: 52.3% vs 75.9% (p<0.005). Multivariable HR for death: 2.010 (95% CI 1.303–3.100; p=0.002). Associations also seen with serosal invasion (p=0.002), lymph-node metastasis (p=0.002), venous invasion (p=0.019), and stage (p=0.015) (suematsu2022clinicalsignificanceof pages 2-4, suematsu2022clinicalsignificanceof pages 1-2, suematsu2022clinicalsignificanceof pages 4-5)	Suematsu 2022	https://doi.org/10.21873/anticanres.16097	2022-12
Clinical association: HNSC (TCGA)	In TCGA HNSC, SEC11A was upregulated in primary tumors (n=518) vs adjacent normals (n=44). High-expression group had more PFS events 117/259 (22.6%) vs 80/259 (15.4%), p=0.001, and more DSS events 80/246 (16.3%) vs 50/246 (10.2%), p=0.003. Continuous-expression multivariable HRs: PFS 2.075 (95% CI 1.447–2.977; p<0.001) and DSS 2.023 (95% CI 1.284–3.187; p=0.002). Expression correlated with copy number, r=0.53 (p<0.001) (hu2022signalpeptidasecomplex pages 1-2, hu2022signalpeptidasecomplex pages 6-9, hu2022signalpeptidasecomplex pages 2-4)	Hu 2022	https://doi.org/10.1371/journal.pone.0269166	2022-06

Table: This table condenses the main mechanistic, structural, and clinical findings for human SEC11A/SPC18. It is useful as a quick reference linking SEC11A’s role in the signal peptidase complex to recent functional studies and quantitative cancer associations.

Key quantitative points include (i) SPC substrate-set scale (~3,000 human SPs) (liaci2021structureofthe pages 10-12), (ii) membrane thinning from ~4 nm to ~2.3–2.6 nm in the TM window region (as described in associated figure context) (liaci2021structureofthe media 1e096f5b), and (iii) cancer prognosis effect sizes (gastric cancer multivariable HR ~2.0; TCGA-HNSC multivariable HR ~2.0, and copy-number correlation r=0.53). (suematsu2022clinicalsignificanceof pages 2-4, hu2022signalpeptidasecomplex pages 2-4)

8) Limitations of the current evidence base (for SEC11A specifically)

The most detailed mechanistic/structural evidence in this corpus focuses on the SPC as a complex, with SEC11A interpreted as the proteolytic subunit in one paralog; residue-level discussion is largely for SEC11 paralogs collectively (SEC11A/C). (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)
The most directly SEC11A-specific and quantitative clinical analyses retrieved here are from 2022 rather than 2023–2024, although they remain recent and provide effect sizes not typically available in narrative reviews. (suematsu2022clinicalsignificanceof pages 2-4, hu2022signalpeptidasecomplex pages 2-4)

References (URLs and publication dates)

Liaci AM et al. Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage. 2021-01. https://doi.org/10.2139/ssrn.3778304 (liaci2021structureofthe pages 1-3, liaci2021structureofthe pages 10-12)
Zanotti A. Characterisation of the human signal peptidase complex as a quality control enzyme for membrane proteins. 2023-01. https://doi.org/10.11588/heidok.00033417 (zanotti2023characterisationofthe pages 53-57)
Chung Y et al. Spc2 modulates substrate- and cleavage site-selection in the yeast signal peptidase complex. J Cell Biol. 2024-11. https://doi.org/10.1083/jcb.202211035 (chung2024spc2modulatessubstrate pages 1-2)
Suematsu H et al. Clinical Significance of SEC11A Expression in Patients With Locally Advanced Gastric Cancer. Anticancer Research. 2022-12. https://doi.org/10.21873/anticanres.16097 (suematsu2022clinicalsignificanceof pages 2-4)
Hu C et al. Signal peptidase complex catalytic subunit SEC11A upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma. PLoS ONE. 2022-06. https://doi.org/10.1371/journal.pone.0269166 (hu2022signalpeptidasecomplex pages 2-4)

References

(liaci2021structureofthe pages 1-3): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe pages 3-4): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(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.
(liaci2021structureofthe pages 7-8): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe pages 10-12): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(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.
(liaci2021structureofthe media 1e096f5b): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe media e7dabb13): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(liaci2021structureofthe media 5164c33e): A. Manuel Liaci, Barbara Steigenberger, Sem Tamara, Paulo Cesar Telles de Souza, Mariska Gröllers-Mulderij, Patrick Ogrissek, Siewert Jan Marrink, Richard Scheltema, and Friedrich Förster. Structure of the human signal peptidase complex reveals the determinants for signal peptide cleavage. Jan 2021. URL: https://doi.org/10.2139/ssrn.3778304, doi:10.2139/ssrn.3778304. This article has 148 citations.
(suematsu2022clinicalsignificanceof pages 2-4): HIDEAKI SUEMATSU, KENTARO SAKAMAKI, NAOHIDE OUE, YUKIHIKO HIROSHIMA, YAYOI KIMURA, SHIZUNE ONUMA, ITARU HASHIMOTO, SHINSUKE NAGASAWA, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, YASUSHI RINO, MUNETAKA MASUDA, WATARU YASUI, YOHEI MIYAGI, and TAKASHI OSHIMA. Clinical significance of sec11a expression in patients with locally advanced gastric cancer. AntiCancer Research, 42:5885-5890, Dec 2022. URL: https://doi.org/10.21873/anticanres.16097, doi:10.21873/anticanres.16097. This article has 10 citations and is from a peer-reviewed journal.
(suematsu2022clinicalsignificanceof pages 4-5): HIDEAKI SUEMATSU, KENTARO SAKAMAKI, NAOHIDE OUE, YUKIHIKO HIROSHIMA, YAYOI KIMURA, SHIZUNE ONUMA, ITARU HASHIMOTO, SHINSUKE NAGASAWA, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, YASUSHI RINO, MUNETAKA MASUDA, WATARU YASUI, YOHEI MIYAGI, and TAKASHI OSHIMA. Clinical significance of sec11a expression in patients with locally advanced gastric cancer. AntiCancer Research, 42:5885-5890, Dec 2022. URL: https://doi.org/10.21873/anticanres.16097, doi:10.21873/anticanres.16097. This article has 10 citations and is from a peer-reviewed journal.
(hu2022signalpeptidasecomplex pages 1-2): Chunmei Hu, Jiangang Fan, Gang He, Chuan Dong, Shijie Zhou, and Yun Zheng. Signal peptidase complex catalytic subunit sec11a upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma. PLoS ONE, 17:e0269166, Jun 2022. URL: https://doi.org/10.1371/journal.pone.0269166, doi:10.1371/journal.pone.0269166. This article has 5 citations and is from a peer-reviewed journal.
(hu2022signalpeptidasecomplex pages 2-4): Chunmei Hu, Jiangang Fan, Gang He, Chuan Dong, Shijie Zhou, and Yun Zheng. Signal peptidase complex catalytic subunit sec11a upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma. PLoS ONE, 17:e0269166, Jun 2022. URL: https://doi.org/10.1371/journal.pone.0269166, doi:10.1371/journal.pone.0269166. This article has 5 citations and is from a peer-reviewed journal.
(hu2022signalpeptidasecomplex pages 9-11): Chunmei Hu, Jiangang Fan, Gang He, Chuan Dong, Shijie Zhou, and Yun Zheng. Signal peptidase complex catalytic subunit sec11a upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma. PLoS ONE, 17:e0269166, Jun 2022. URL: https://doi.org/10.1371/journal.pone.0269166, doi:10.1371/journal.pone.0269166. This article has 5 citations and is from a peer-reviewed journal.
(suematsu2022clinicalsignificanceof pages 1-2): HIDEAKI SUEMATSU, KENTARO SAKAMAKI, NAOHIDE OUE, YUKIHIKO HIROSHIMA, YAYOI KIMURA, SHIZUNE ONUMA, ITARU HASHIMOTO, SHINSUKE NAGASAWA, TORU AOYAMA, TAKANOBU YAMADA, HIROSHI TAMAGAWA, TAKASHI OGATA, YASUSHI RINO, MUNETAKA MASUDA, WATARU YASUI, YOHEI MIYAGI, and TAKASHI OSHIMA. Clinical significance of sec11a expression in patients with locally advanced gastric cancer. AntiCancer Research, 42:5885-5890, Dec 2022. URL: https://doi.org/10.21873/anticanres.16097, doi:10.21873/anticanres.16097. This article has 10 citations and is from a peer-reviewed journal.
(hu2022signalpeptidasecomplex pages 6-9): Chunmei Hu, Jiangang Fan, Gang He, Chuan Dong, Shijie Zhou, and Yun Zheng. Signal peptidase complex catalytic subunit sec11a upregulation is a biomarker of poor prognosis in patients with head and neck squamous cell carcinoma. PLoS ONE, 17:e0269166, Jun 2022. URL: https://doi.org/10.1371/journal.pone.0269166, doi:10.1371/journal.pone.0269166. This article has 5 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

zanotti2023characterisationofthe pages 53-57
liaci2021structureofthe pages 10-12
suematsu2022clinicalsignificanceof pages 2-4
hu2022signalpeptidasecomplex pages 2-4
liaci2021structureofthe pages 1-3
liaci2021structureofthe pages 3-4
liaci2021structureofthe pages 7-8
suematsu2022clinicalsignificanceof pages 4-5
hu2022signalpeptidasecomplex pages 1-2
hu2022signalpeptidasecomplex pages 9-11
suematsu2022clinicalsignificanceof pages 1-2
hu2022signalpeptidasecomplex pages 6-9
https://doi.org/10.21873/anticanres.16097
https://doi.org/10.1371/journal.pone.0269166
https://doi.org/10.2139/ssrn.3778304
https://doi.org/10.1083/jcb.202211035
https://doi.org/10.11588/heidok.00033417
https://doi.org/10.2139/ssrn.3778304,
https://doi.org/10.11588/heidok.00033417,
https://doi.org/10.1083/jcb.202211035,
https://doi.org/10.21873/anticanres.16097,
https://doi.org/10.1371/journal.pone.0269166,

📚 Additional Documentation

Notes

(SEC11A-notes.md)

SEC11A (P67812, SPC18) review notes

Identity / overview

SEC11A is a single-pass type II ER membrane protein and one of the two catalytic serine-endopeptidase
subunits of the human signal peptidase complex (SPC). It is the proteolytic subunit of the SPC-A paralog
(with accessory subunits SPCS1, SPCS2, SPCS3) and cleaves N-terminal signal/leader peptides from secretory
and membrane pre-proteins as they are translocated into the ER lumen (EC 3.4.21.89). Peptidase family S26B;
Ser/His/Asp charge-relay catalytic triad (catalytic Ser-56). The other catalytic paralog is SEC11C (SPC-C).

UniProt FUNCTION: "Catalytic component of the signal peptidase complex (SPC) which catalyzes the cleavage
of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the
endoplasmic reticulum"; "Specifically cleaves N-terminal signal peptides that contain a hydrophobic
alpha-helix (h-region) shorter than 18-20 amino acids" [file:human/SEC11A/SEC11A-uniprot.txt].
SUBUNIT: "Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit
SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 ... Within the complex, interacts with SPCS2
and SPCS3" [file:human/SEC11A/SEC11A-uniprot.txt].
SUBCELLULAR LOCATION: "Endoplasmic reticulum membrane ... Single-pass type II membrane protein"
[file:human/SEC11A/SEC11A-uniprot.txt].
Catalytic triad ACT_SITE 56/96/122; MUTAGEN S56A "Loss of catalytic activity"; CTS helix (165-176)
essential for catalysis [file:human/SEC11A/SEC11A-uniprot.txt].

Key functional evidence

Structure of the human SPC: PMID:34388369 (Liaci et al., Mol Cell 2021): "the human SPC exists in two
functional paralogs with distinct proteolytic subunits"; "The active site is formed by a catalytic triad
and abuts the ER membrane, where a transmembrane window collectively formed by all subunits locally thins
the bilayer"; specificity for SPs based on hydrophobic segment length PMID:34388369. EXP/IDA evidence
for catalytic and complex-membership annotations.

Annotation review decisions

Core MF: serine-type endopeptidase activity (GO:0004252) / signal peptidase activity (GO:0009003);
generic peptidase activity (GO:0008233) ACCEPTed as parent.
Core CC: signal peptidase complex (GO:0005787); ER membrane (GO:0005789); generic membrane (GO:0016020)
KEEP_AS_NON_CORE.
Core BP: signal-peptide cleavage captured by protein processing (GO:0016485) / protein maturation
(GO:0051604). Note: GO:0006465 (signal peptide processing) is in the UniProt DR block but NOT in the GOA
tsv, so it cannot be added as an existing_annotation; core_functions therefore uses GO:0016485 which is
present.
GO:0009615 response to virus (TAS, Reactome RSV pathway): MARK_AS_OVER_ANNOTATED — reflects generic
signal peptidase processing of viral substrates, not a dedicated antiviral response.
protein binding (GO:0005515) IPI rows: high-throughput captures (HuRI PMID:32296183, BioPlex
PMID:33961781, cell-map PMID:40205054) + intra-complex SPCS2/SPCS3 (PMID:34388369). KEEP_AS_NON_CORE.

Falcon deep-research findings (incorporated 2026-06)

The Falcon report (Edison Scientific) for SEC11A largely recapitulates literature already in the
review: Liaci 2021 SPC cryo-EM (PMID:34388369), the SPC quality-control function (PMID:36454823),
cavinafungin (PMID:28423309), the Chung 2024 Spc2 yeast mechanism (PMID:39565596), and the two
cancer biomarker papers (gastric PMID:36456166; HNSC PMID:35653344). All were already incorporated.

NEW reference added: competitive inhibition of ER signal peptidase by non-cleavable preproteins.
The non-cleavable variant "binds to the catalytic SPase subunit SEC11A, inhibiting SPase activity
in a dose-dependent manner" and impairs processing in trans, including of viral polypeptides; the
authors propose eukaryotic SPase as an antiviral drug target PMID:26446786. PubMed-
verified (DOI 10.1074/jbc.M115.692350, J Biol Chem 2015). Added to references (relevance MEDIUM,
correctness VERIFIED). Not in GOA, so no new GO annotation; supports SEC11A's signal peptidase
activity (GO:0009003/GO:0004252) and its druggability. The Falcon report cites this paper only in
its SEC11C report, but the abstract names SEC11A specifically.
Falcon quantitative context (already consistent with review): SPC processes ~3,000 human signal
peptides; membrane-thinning TM window reduces bilayer from ~4 nm to ~2.3-2.6 nm; ~1,500 membrane
proteins predicted to carry cryptic SPC cleavage sites PMID:36454823. No annotation change.
Falcon's "ssrn.3778304" DOI for the Liaci structure is the preprint of the published Mol Cell paper
already cited as PMID:34388369; no separate reference added.

Pn Notes

(SEC11A-pn-notes.md)

SEC11A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P67812
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/SEC11A/SEC11A-ai-review.yaml
AIGR review HTML: missing - genes/human/SEC11A/SEC11A-ai-review.html
Gene notes: present - genes/human/SEC11A/SEC11A-notes.md
GOA TSV: present - genes/human/SEC11A/SEC11A-goa.tsv
UniProt record: present - genes/human/SEC11A/SEC11A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/SEC11A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/SEC11A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/SEC11A/SEC11A-deep-research-falcon.md

AIGR Review Snapshot

Description: 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.
Existing/core annotation action counts: ACCEPT: 20; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

Consistency: Strong agreement. Deep research, review YAML, and PN all identify SEC11A as the catalytic serine-endopeptidase subunit of the SPC-A paralog (Ser-56 triad, EC 3.4.21.89, membrane-thinning specificity). PN's "ER signal peptidase" node correctly captures complex membership. No contradictions.
PN story / NEW pressure: PN asserts only complex membership (GO:0005787) and the broad transport class (GO:0015031). Both already captured: review has GO:0005787 (IDA/IPI/IBA/IEA) plus the catalytic MF (GO:0009003 signal peptidase activity, GO:0004252 serine-type endopeptidase activity, EXP/IDA) — the latter being the gene's distinguishing function, which the PN node (a CC-level membership) does NOT assert. So PN under-specifies SEC11A's catalytic MF rather than over-reaching. No NEW term needed. Conclude: already captured (review is richer than PN).
Evidence alignment: PN row carries no titles; review's catalytic evidence (PMID:34388369 cryo-EM/triad; Reactome signalase reactions; PMID:36454823 QC; PMID:28423309 cavinafungin) and falcon deep research (liaci2021) all converge on the catalytic identity. Congruent.
Verdict: CONSISTENT; PN captures CC membership but omits the catalytic MF that defines SEC11A (already in review). No edit required.

Full Consistency Review

UniProt: P67812 (SPC18) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE
PN placement: 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).
Consistency: Strong agreement. Deep research, review YAML, and PN all identify SEC11A as the catalytic serine-endopeptidase subunit of the SPC-A paralog (Ser-56 triad, EC 3.4.21.89, membrane-thinning specificity). PN's "ER signal peptidase" node correctly captures complex membership. No contradictions.
PN story / NEW pressure: PN asserts only complex membership (GO:0005787) and the broad transport class (GO:0015031). Both already captured: review has GO:0005787 (IDA/IPI/IBA/IEA) plus the catalytic MF (GO:0009003 signal peptidase activity, GO:0004252 serine-type endopeptidase activity, EXP/IDA) — the latter being the gene's distinguishing function, which the PN node (a CC-level membership) does NOT assert. So PN under-specifies SEC11A's catalytic MF rather than over-reaching. No NEW term needed. Conclude: already captured (review is richer than PN).
Mapping strategy: Mapping is correct but blunt: the node maps the whole "ER signal peptidase" group to the CC GO:0005787, which conflates catalytic (SEC11A/C) and accessory (SPCS1/2/3) members. For SEC11A specifically the catalytic peptidase MF is the salient function and is not represented at the node. Node need not change (GO:0005787 is right for all four), but a node-level note should distinguish catalytic-subunit MF (GO:0009003/GO:0004252) for SEC11A/C. GO:0015031 protein transport is acceptably broad. No precedent-style over-reach.
Evidence alignment: PN row carries no titles; review's catalytic evidence (PMID:34388369 cryo-EM/triad; Reactome signalase reactions; PMID:36454823 QC; PMID:28423309 cavinafungin) and falcon deep research (liaci2021) all converge on the catalytic identity. Congruent.
Verdict: CONSISTENT; PN captures CC membership but omits the catalytic MF that defines SEC11A (already in review). No edit required.
Recommended edits: [MAP] At the "ER signal peptidase" node, annotate that catalytic subunits SEC11A/SEC11C additionally project signal peptidase MF (GO:0009003 / GO:0004252), distinct from accessory subunits — so the node does not flatten catalytic vs accessory members.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/SEC11A/SEC11A-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | ER signal peptidase

UniProt: P67812
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|ER signal peptidase
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0005787 signal peptidase complex]
  rationale: This PN group denotes ER signal peptidase complex components. The matching GO cellular-component term is the direct propagation target.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0005787 signal peptidase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Protein transport|ER signal peptidase

Note

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.

📄 View Raw YAML

id: P67812
gene_symbol: SEC11A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0005787
    label: signal peptidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: SEC11A is the catalytic subunit of the signal peptidase complex (SPC-A paralog); membership in the SPC is its defining, conserved cellular component.
    action: ACCEPT
    reason: Core cellular component; SEC11A is the proteolytic subunit of the signal peptidase complex.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-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:0008233
    label: peptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: SEC11A 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 SEC11A's catalytic role.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-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: 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.
    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/SEC11A/SEC11A-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog A (SPC-A)
- 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; SEC11A is a single-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-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/SEC11A/SEC11A-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 SEC11A's specific catalytic function and is experimentally supported (EXP).
    action: ACCEPT
    reason: Core molecular function; SEC11A is the catalytic signal peptidase of the SPC (EC 3.4.21.89).
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-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: SEC11A 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/SEC11A/SEC11A-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- 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 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/SEC11A/SEC11A-uniprot.txt
      supporting_text: 'P67812; 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/SEC11A/SEC11A-uniprot.txt
      supporting_text: 'P67812; P61009: SPCS3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34388369
  qualifier: enables
  review:
    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.
    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/SEC11A/SEC11A-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/SEC11A/SEC11A-uniprot.txt
      supporting_text: 'P67812; P61009: SPCS3'
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9829030
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental signal peptidase activity.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: catalyzes the cleavage of N-terminal signal sequences
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9932162
  qualifier: enables
  review:
    summary: Reactome curation of SEC11A serine-endopeptidase activity (removal of the CDH1 signal peptide); consistent with its core catalytic function.
    action: ACCEPT
    reason: Correct core molecular function; redundant with experimental signal peptidase activity.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: catalyzes the cleavage of N-terminal signal sequences
- 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 SEC11A within the assembled signal peptidase complex (SPC-A) with SPCS1/2/3; defining cellular component.
    action: ACCEPT
    reason: Core cellular component; SEC11A is the catalytic subunit of the structurally resolved SPC-A complex.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog A (SPC-A)
- 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 SEC11A in the ER membrane, with the active site abutting the bilayer; direct experimental localization.
    action: ACCEPT
    reason: Core localization with direct experimental support; SEC11A acts at the ER membrane.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: nascent proteins as they are translocated into the lumen of
        the endoplasmic reticulum
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IDA
  original_reference_id: PMID:34388369
  qualifier: involved_in
  review:
    summary: SEC11A 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 GO:0006465 (signal peptide processing) better captures SEC11A'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/SEC11A/SEC11A-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-56) that SEC11A is the catalytic signal peptidase of the SPC. This is the core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; SEC11A is the 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:0009615
    label: response to virus
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9820965
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: catalyzes the cleavage of N-terminal signal sequences
- 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 SEC11A 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 SEC11A is the catalytic subunit within the assembled SPC-A; defining cellular component.
    action: ACCEPT
    reason: Core cellular component with direct experimental (IDA) support.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-uniprot.txt
      supporting_text: Component of the signal peptidase complex paralog A (SPC-A)
- 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, SEC11A 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 GO:0006465 (signal peptide processing) better captures SEC11A'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 SEC11A 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/SEC11A/SEC11A-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 SEC11A 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/SEC11A/SEC11A-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 SEC11A ER membrane localization (NS4B signalase cleavage).
    action: ACCEPT
    reason: Correct core localization; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/SEC11A/SEC11A-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: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: SEC11A is the catalytic subunit of SPC-A (with accessory subunits SPCS1, SPCS2, SPCS3); Ser-56 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 SEC11A 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, which are abundant in the human
      membrane proteome; this post-translocational cleavage synergizes with ER-associated
      degradation (ERAD) to maintain membrane protein homeostasis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1126/science.abo5672, Science 2022). Establishes
      a previously unknown membrane-protein quality-control function of the SPC catalytic
      core (SEC11A/C); SEC11A knockdown alone did not abolish noncanonical cleavage,
      consistent with SEC11A/SEC11C redundancy. Not in GOA; informs BP context but
      no new SEC11A-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 SEC11A'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 SEC11A 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, e.g. preproinsulin pPI-F25P) is translocated
      across the ER membrane where it binds the catalytic SPase subunit SEC11A and
      inhibits signal peptidase activity in a dose-dependent manner, impairing in trans
      the processing/maturation of co-expressed preproteins and of viral polypeptides;
      this identifies eukaryotic SPase (human SEC11A) as a tractable therapeutic/antiviral
      target.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:26446786, DOI 10.1074/jbc.M115.692350, J Biol
      Chem 2015). Abstract explicitly names SEC11A as the catalytic SPase subunit to
      which a non-cleavable preprotein binds, providing functional/mechanistic support
      for SEC11A's signal peptidase activity and its druggability; not in GOA, no new
      core GO annotation added.
- id: PMID:36456166
  title: Clinical Significance of SEC11A Expression in Patients With Locally Advanced
    Gastric Cancer.
  findings:
  - statement: In locally advanced gastric cancer (n=253), high SEC11A mRNA expression
      was associated with worse 5-year overall survival and was an independent predictor
      of poor prognosis in multivariate analysis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.21873/anticanres.16097, Anticancer Res 2022).
      Disease-association/biomarker study; SEC11A overexpression as a prognostic marker
      does not establish a dedicated GO biological process and yields no new core annotation.
- id: PMID:35653344
  title: Signal peptidase complex catalytic subunit SEC11A upregulation is a biomarker
    of poor prognosis in patients with head and neck squamous cell carcinoma.
  findings:
  - statement: In TCGA head and neck squamous cell carcinoma, SEC11A was upregulated
      in tumors versus adjacent normal tissue and higher SEC11A expression independently
      predicted poorer progression-free and disease-specific survival; expression
      correlated with SEC11A copy number.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1371/journal.pone.0269166, PLoS ONE 2022).
      Biomarker/disease-association study; supports amplification-associated overexpression
      but provides no new core GO annotation for SEC11A.
- id: Reactome:R-HSA-422051
  title: Cleavage of the signal peptide of Preproghrelin
  findings: []
- id: Reactome:R-HSA-9820965
  title: Respiratory syncytial virus (RSV) genome replication, transcription and translation
  findings: []
- id: Reactome:R-HSA-9829030
  title: Nascent F signal peptide is cleaved at ER membrane
  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: Reactome:R-HSA-9932162
  title: Removal of CDH1 signal peptide
  findings: []
- id: file:human/SEC11A/SEC11A-uniprot.txt
  title: UniProt entry P67812 (SC11A_HUMAN), Signal peptidase complex catalytic subunit
    SEC11A
  findings:
  - statement: SEC11A is the catalytic subunit of the signal peptidase complex paralog A (SPC-A) 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-56), 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-A 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/SEC11A/SEC11A-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 SEC11A (SPC-A) versus SEC11C (SPC-C) paralogous signal peptidase complexes in human cells, and do they serve distinct subsets of the secretory proteome?
- question: How does the SPC's local thinning of the ER membrane mechanistically couple signal-peptide h-region length to catalytic engagement by SEC11A?
suggested_experiments:
- description: 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.
- description: 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.

SEC11A

Gene Description

Existing Annotations Review

Core Functions

Catalytic serine-endopeptidase subunit of the ER signal peptidase complex (SPC-A 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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human SEC11A (SPC18) Functional Annotation (UniProt P67812)

1) Target verification (identity, organism, family)

2) Key concepts and current understanding

2.1 Signal peptides and their canonical cleavage rules

2.2 SEC11A as the catalytic component of the eukaryotic SPC

2.3 Complex composition, architecture, and subunit roles

2.4 Enzymatic mechanism: catalytic triad and reaction

2.5 Substrate specificity: “measuring” the signal peptide h-region

3) Subcellular localization and pathway context

4) Recent developments and latest research (emphasis 2023–2024)

4.1 2024: Noncatalytic subunits modulate substrate and cleavage-site selection

4.2 2023: SPC as a membrane-protein quality-control enzyme and noncanonical cleavage

4.3 Structural visualization (supporting evidence)

5) Current applications and real-world implementations

5.1 Biomarker applications in oncology (prognostic associations)

5.2 Mechanistic translational relevance: secretion and growth-factor signaling

6) Expert opinions and analysis (authoritative interpretation from sources)

6.1 Mechanistic consensus from structural work

6.2 Emerging view of broader SPC roles

7) Relevant statistics and data highlights

8) Limitations of the current evidence base (for SEC11A specifically)

References (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

SEC11A (P67812, SPC18) review notes

Identity / overview

Key functional evidence

Annotation review decisions

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

SEC11A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Protein transport | ER signal peptidase

Projected GO annotations (2)

Note

📄 View Raw YAML