SPCS3 (signal peptidase complex subunit 3, also SPC22/23, the microsomal signal peptidase 22/23 kDa subunit) is a 180 aa single-pass type II endoplasmic reticulum membrane protein that is one of the three non-catalytic accessory subunits (with SPCS1 and SPCS2) of the eukaryotic ER signal peptidase complex (SPC). The SPC removes N-terminal signal sequences from secretory and membrane preproteins as they are translocated into the ER lumen; catalysis resides in the SEC11A or SEC11C subunits. SPCS3 has a single N-terminal transmembrane helix and a large lumenal domain, and although not catalytic itself it is essential for SPC catalytic activity, thought to stabilize and position the catalytic center near the lumenal surface of the membrane. Together with the other subunits it contributes to the transmembrane window that locally thins the ER bilayer and sets the complex's selectivity for short signal-peptide hydrophobic regions. SPCS3 also acts as a host factor required for efficient production of flaviviruses (West Nile, Japanese encephalitis, Dengue type 2, and yellow fever viruses).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005787 signal peptidase complex | IBA GO_REF:0000033 | ACCEPT | Summary: SPCS3 is a constitutive accessory subunit of the ER signal peptidase complex; the phylogenetic assignment reflects its core identity. Reason: Core complex membership, supported experimentally by cryo-EM and ComplexPortal curation. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 |
| GO:0045047 protein targeting to ER | IBA GO_REF:0000033 | REMOVE | Summary: SPCS3 does not target proteins to the ER; as part of the signal peptidase complex it acts on already-translocating substrates to cleave the signal peptide. The phylogenetic term is mis-specified; the accurate process is signal peptide cleavage, i.e. protein processing, which this gene already carries as an ACCEPTed IDA annotation (GO:0016485, PMID:34388369). Reason: The SPC acts downstream of ER targeting. UniProt/ComplexPortal annotate this activity as signal peptide processing (GO:0006465). GO has since obsoleted GO:0006465 because it represents the molecular function signal peptidase activity (GO:0009003, captured in core_functions); its live process-level parent is protein processing (GO:0016485), which is already an ACCEPTed IDA annotation on this gene (PMID:34388369). A MODIFY to GO:0016485 would duplicate that row, so the mis-specified IBA term is removed rather than replaced. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning assignment of ER localization; correct but less specific than the ER membrane term. Reason: Correct localization; the more specific GO:0005789 (ER membrane) better captures the multi-pass topology. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005787 signal peptidase complex | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment to the signal peptidase complex, consistent with experimental evidence. Reason: Correct core complex membership; redundant with experimental IPI/IBA evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3 |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SPCS3 is an ER membrane protein; the subcellular-location-based electronic annotation is correct and reflects the core localization. Reason: Core localization, supported by structure (PMID:34388369) and ortholog topology. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane localization, a parent of the more informative ER membrane term. Reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SPCS3 localization. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Single-pass type II membrane protein |
| GO:0005515 protein binding | IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis... | KEEP AS NON CORE | Summary: High-throughput interaction proteomics capturing SPCS3 binding to ATXN1; a real interaction but the bare protein binding term is uninformative. Reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P54253: ATXN1 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput human interactome capturing SPCS3 binding to SEC11C; a genuine intra-complex interaction but the bare protein binding term is uninformative. Reason: Real intra-complex interaction (SEC11C) but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; Q9BY50: SEC11C |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegenerative-disease interactome capturing SPCS3 binding to HTT/ATXN1; real interactions but the bare protein binding term is uninformative. Reason: High-throughput interactome capture; bare protein binding is uninformative and not the core function. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P42858: HTT |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Proteome-scale BioPlex interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; P67812: SEC11A |
| GO:0005515 protein binding | IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ... | KEEP AS NON CORE | Summary: Interactions with the other SPC subunits (SEC11A/SEC11C, SPCS1, SPCS2) captured during the structural study; bare protein binding is uninformative although the intra-complex interactions are genuine. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Within the complex, interacts with SEC11A or SEC11C and SPCS1 |
| 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 interactome capturing SPCS3 binding to SEC11A/SEC11C; genuine intra-complex interactions but the bare protein binding term is uninformative. Reason: Real intra-complex interactions but bare protein binding is uninformative; complex membership is captured by GO:0005787. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt P61009; Q9BY50: SEC11C |
| GO:0005787 signal peptidase complex | IPI PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: ComplexPortal annotation of SPCS3 as a component of the signal peptidase complex, based on the cryo-EM structure of the human SPC. Reason: Definitive experimental (structural) evidence for SPC membership; the core identity of SPCS3. Supporting Evidence: PMID:34388369 the human SPC exists in two functional paralogs with distinct proteolytic subunits |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: Direct (structural) evidence places SPCS3 in the ER membrane as part of the SPC; correct core localization. Reason: IDA-supported ER membrane localization consistent with the membrane-embedded SPC structure. Supporting Evidence: PMID:34388369 a transmembrane window collectively formed by all subunits locally thins the bilayer |
| GO:0016485 protein processing | IDA PMID:34388369 Structure of the human signal peptidase complex reveals the ... | ACCEPT | Summary: SPCS3 participates in proteolytic processing of preproteins as part of the signal peptidase complex; more specifically, the SPC cleaves N-terminal signal peptides (the former GO:0006465 signal peptide processing, now obsolete in GO, for which protein processing is the live process term). Reason: Correct involvement in the SPC's proteolytic processing of substrates; supported by the structural study and ComplexPortal curation. The core process is signal peptide cleavage, which GO now represents with this protein processing term (GO:0016485) after obsoleting GO:0006465 signal peptide processing. Supporting Evidence: PMID:34388369 the determinants for signal peptide cleavage |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of ER membrane localization from an ortholog; consistent with stronger experimental evidence. Reason: Correct core localization, redundant with IDA/IEA evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0019082 viral protein processing | IMP PMID:27383988 A CRISPR screen defines a signal peptide processing pathway ... | KEEP AS NON CORE | Summary: A genome-wide CRISPR screen showed SPCS3 (with other SPCS proteins) is required for proper processing of flavivirus structural proteins and virion production; a real experimental phenotype but a secondary host-pathogen role. Reason: Experimentally supported viral host-factor role; secondary to SPCS3's core function in cellular signal peptide processing. Supporting Evidence: PMID:27383988 a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles |
| GO:0006508 proteolysis | IDA PMID:27499293 Inverting the Topology of a Transmembrane Protein by Regulat... | KEEP AS NON CORE | Summary: Experimental annotation linking SPCS3 to proteolysis, made by a curator with access to the full text (a study of ER translocation and regulated membrane-protein/CREB3L1 cleavage). The general proteolysis term reflects SPCS3's role in the proteolytic signal peptidase complex; SPCS3 is essential for SPC catalytic activity though not itself the protease. Reason: General parent term; SPCS3 is a non-catalytic but essential subunit of the proteolytic SPC. The informative process is protein processing (GO:0016485; GO:0006465 signal peptide processing is now obsolete). Experimental IDA retained (full text not in cache), kept as non-core given the more specific available terms. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-422051 | ACCEPT | Summary: Reactome curation of SPCS3 ER membrane localization (preproghrelin signal peptide cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9918795 | ACCEPT | Summary: Reactome curation of SPCS3 ER membrane localization (flavivirus signalase cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9918871 | ACCEPT | Summary: Reactome curation of SPCS3 ER membrane localization (signalase cleavage context). Reason: Correct core localization; redundant with experimental evidence. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | ACCEPT | Summary: Direct fluorescent fusion-protein localization (LIFEdb) placing SPCS3 in the ER; correct though less specific than ER membrane. Reason: IDA-supported ER localization consistent with the ER membrane annotations. Supporting Evidence: file:human/SPCS3/SPCS3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
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Download this section (compressed HTML)Q: By what structural mechanism does the SPCS3 lumenal domain become essential for SEC11 catalytic activity, in contrast to the dispensable SPCS1?
Q: Is the flavivirus dependence on SPCS3 attributable to its general signal-peptidase role or to substrate-specific processing of viral structural proteins?
Experiment: Reconstitute SPC with and without SPCS3 and measure signal-peptidase activity to quantify its requirement and define which substrate classes most depend on it.
Experiment: Structure-guided mutagenesis of the SPCS3 lumenal domain at the SEC11 interface, with activity assays, to test the proposed active-center stabilization mechanism.
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