id: P43307 gene_symbol: SSR1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: SSR1 encodes Translocon-associated protein subunit alpha (TRAP-alpha), a single-pass type I ER membrane glycoprotein that is a core component of the heterotetrameric TRAP complex (TRAP-alpha/beta/gamma/delta, encoded by SSR1-4). The TRAP complex stably associates with the Sec61 protein-conducting channel and ribosomes at the ER membrane, facilitating co-translational translocation of secretory and membrane proteins, particularly those with weak or atypical signal peptides. TRAP-alpha features a large N-terminal luminal domain positioned beneath the Sec61 channel exit site and a single long transmembrane helix that contacts Sec61. The complex coordinates with the oligosaccharyltransferase (OST) to couple translocation with N-glycosylation. TRAP-alpha also participates in ER quality control and ERAD pathways. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: IBA annotation for ER localization based on phylogenetic inference from PANTHER. TRAP-alpha is well-established as an ER-resident protein across eukaryotes. Recent cryo-EM structures confirm TRAP as a core ER translocon component [SSR1-deep-research-falcon.md]. action: ACCEPT reason: Core localization annotation. TRAP-alpha is definitively an ER membrane protein. The IBA annotation is well-supported by extensive structural and biochemical evidence showing TRAP-alpha as a core component of the ER translocon complex [Pauwels et al. 2023; Karki et al. 2023; PMID:36697828]. supported_by: - reference_id: PMID:8050590 supporting_text: "The alpha-subunit of the TRAP complex (TRAP alpha) is a single-spanning membrane protein of the endoplasmic reticulum (ER) which is found in proximity of nascent polypeptide chains translocating across the membrane." - reference_id: file:human/SSR1/SSR1-deep-research-falcon.md supporting_text: 'model: Edison Scientific Literature' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: IEA annotation based on InterPro TRAP_alpha domain and UniProt subcellular location annotation. This is the specific membrane localization. action: ACCEPT reason: Core localization annotation. TRAP-alpha is a single-pass type I membrane protein anchored in the ER membrane. UniProt confirms this topology with a luminal N-terminal domain and cytoplasmic C-terminus. Structural studies confirm ER membrane integration [PMID:36697828]. supported_by: - reference_id: PMID:36697828 supporting_text: "near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) reveals specific interactions of TRAP with other translocon components" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17380188 review: summary: IPI annotation based on interaction with SERPINA1/alpha1-antitrypsin, calnexin (CANX), and SEC61B detected in the context of ER stress and ERAD studies. action: MODIFY reason: While the protein binding annotation reflects genuine interactions, it is uninformative. The study shows TRAP complex involvement in ERAD and interaction with misfolded substrates like alpha1-antitrypsin NHK variant. A more specific term capturing the functional interaction would be appropriate. proposed_replacement_terms: - id: GO:0140597 label: protein localization to ribosome-translocon complex additional_reference_ids: - PMID:17380188 supported_by: - reference_id: PMID:17380188 supporting_text: "The TRAP complex bound preferentially to misfolded proteins rather than correctly folded wild-type substrates. Thus, the TRAP complex induced by the unfolded protein response pathway might discriminate ERAD substrates from correctly folded substrates, accelerating degradation." - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22314232 review: summary: IPI annotation for interaction with palmitoylated calnexin (CANX). The study demonstrates calnexin association with the ribosome-translocon complex including TRAP components. action: MODIFY reason: The protein binding term is too generic. The interaction with calnexin is functionally significant - palmitoylated calnexin associates with the ribosome-translocon complex to facilitate glycoprotein folding. A more specific MF term should be used. proposed_replacement_terms: - id: GO:0140597 label: protein localization to ribosome-translocon complex supported_by: - reference_id: PMID:22314232 supporting_text: "Palmitoylation mediates the association of calnexin with the ribosome-translocon complex (RTC) leading to the formation of a supercomplex that recruits the actin cytoskeleton, leading to further stabilization of the assembly." - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29568061 review: summary: IPI annotation for interaction with calnexin detected by AP-MS and BioID proximity labeling methods. action: MODIFY reason: High-throughput interaction study confirming calnexin-TRAP association. The generic protein binding term is uninformative - should be captured by more specific translocon-related terms. proposed_replacement_terms: - id: GO:0140597 label: protein localization to ribosome-translocon complex supported_by: - reference_id: PMID:29568061 supporting_text: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 review: summary: IPI annotation from OpenCell study detecting interactions with calnexin and SEC61B via endogenous tagging. action: MODIFY reason: High-throughput proteomics confirming established TRAP complex interactions. The generic protein binding is uninformative for understanding function. These represent structural associations within the translocon complex. proposed_replacement_terms: - id: GO:0140597 label: protein localization to ribosome-translocon complex supported_by: - reference_id: PMID:35271311 supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: IEA annotation transferred from mouse ortholog via Ensembl Compara. action: ACCEPT reason: Redundant with IBA annotation but correct. ER localization is core to TRAP-alpha function and well-conserved across mammals. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: IDA annotation based on Human Protein Atlas immunofluorescence data. action: ACCEPT reason: Direct experimental evidence for ER localization. HPA immunofluorescence confirms ER residence of SSR1/TRAP-alpha. - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: NAS original_reference_id: PMID:36697828 review: summary: NAS annotation from ComplexPortal based on cryo-ET structural study visualizing the SEC61-TRAP-OSTA translocon complex. action: ACCEPT reason: Core localization. The structural study provides near-atomic resolution of TRAP within the ER membrane translocon complex [Gemmer et al. 2023]. supported_by: - reference_id: PMID:36697828 supporting_text: "An AlphaFold-based model of TRAP could be fitted unambiguously into the SEC61-OSTA-TRAP translocon map, requiring only minor repositioning of single transmembrane helices" - term: id: GO:0031204 label: post-translational protein targeting to membrane, translocation evidence_type: NAS original_reference_id: PMID:36697828 review: summary: NAS annotation from ComplexPortal. However, this term refers to post-translational translocation, whereas TRAP is primarily involved in co-translational translocation. action: MODIFY reason: The term is inaccurate. TRAP/SSR1 is primarily involved in co-translational protein targeting, not post-translational. The structural study and all functional evidence show TRAP associating with translating ribosomes at the ER. Should be replaced with co-translational targeting term. proposed_replacement_terms: - id: GO:0006613 label: cotranslational protein targeting to membrane supported_by: - reference_id: PMID:36697828 supporting_text: "The dynamic ribosome-translocon complex, which resides at the endoplasmic reticulum (ER) membrane, produces a major fraction of the human proteome" - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1791164 review: summary: TAS annotation from Reactome pathway "Expression of SSR1 (Trap alpha)" indicating ER membrane localization. action: ACCEPT reason: Core localization annotation. Reactome pathway information is consistent with established TRAP-alpha function. - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:8050590 review: summary: TAS annotation from original characterization paper describing TRAP-alpha as an ER protein. action: ACCEPT reason: Primary literature confirming ER localization. This paper established the widespread conservation of TRAP-alpha in eukaryotes. supported_by: - reference_id: PMID:8050590 supporting_text: "The alpha-subunit of the TRAP complex (TRAP alpha) is a single-spanning membrane protein of the endoplasmic reticulum (ER) which is found in proximity of nascent polypeptide chains translocating across the membrane." - term: id: GO:0006613 label: cotranslational protein targeting to membrane evidence_type: TAS original_reference_id: PMID:8050590 review: summary: TAS annotation indicating involvement in co-translational protein targeting based on the original characterization. action: ACCEPT reason: Core function annotation. TRAP-alpha is established as a component of the ribosome-translocon complex facilitating co-translational translocation of nascent polypeptides into the ER. supported_by: - reference_id: PMID:8050590 supporting_text: "The alpha-subunit of the TRAP complex (TRAP alpha) is a single-spanning membrane protein of the endoplasmic reticulum (ER) which is found in proximity of nascent polypeptide chains translocating across the membrane." - term: id: GO:0008284 label: positive regulation of cell population proliferation evidence_type: TAS original_reference_id: PMID:10437777 review: summary: TAS annotation based on observation that TRAP-alpha transcripts are induced by GM-CSF and more abundant in growing vs quiescent cells. action: KEEP_AS_NON_CORE reason: This is a pleiotropic effect rather than a core function. The study shows TRAP-alpha mRNA is upregulated in proliferating cells stimulated by GM-CSF, but this reflects increased demand for protein secretion capacity rather than direct regulation of proliferation. TRAP-alpha's primary function is in protein translocation, not proliferation control. supported_by: - reference_id: PMID:10437777 supporting_text: "Its messenger RNA was more abundant in growing cells than in either factor-deprived cells or quiescent cells" - term: id: GO:0016020 label: membrane evidence_type: TAS original_reference_id: PMID:8050590 review: summary: TAS annotation for generic membrane localization. action: MARK_AS_OVER_ANNOTATED reason: Too general. GO:0005789 (endoplasmic reticulum membrane) is more specific and accurate for TRAP-alpha localization. This generic term adds no additional information. supported_by: - reference_id: PMID:8050590 supporting_text: The N-terminal region of the alpha-subunit of the TRAP complex has a conserved cluster of negative charges. - term: id: GO:0036503 label: ERAD pathway evidence_type: TAS original_reference_id: PMID:17380188 review: summary: Proposed new annotation based on evidence that TRAP complex participates in ERAD by preferentially binding misfolded proteins. action: NEW reason: TRAP complex is induced by ER stress and preferentially binds misfolded proteins, facilitating their degradation via ERAD. This represents an additional function beyond co-translational translocation. supported_by: - reference_id: PMID:17380188 supporting_text: "The TRAP complex bound preferentially to misfolded proteins rather than correctly folded wild-type substrates. Thus, the TRAP complex induced by the unfolded protein response pathway might discriminate ERAD substrates from correctly folded substrates, accelerating degradation." references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:8050590 title: The N-terminal region of the alpha-subunit of the TRAP complex has a conserved cluster of negative charges. findings: - statement: TRAP-alpha is a single-spanning ER membrane protein found in proximity to nascent polypeptides during translocation - statement: Conservation across eukaryotes (human, fish, plants) with preserved charge distribution and glycosylation sites - id: PMID:10437777 title: Translocon-associated protein alpha transcripts are induced by granulocyte-macrophage colony-stimulating factor and exhibit complex alternative polyadenylation. findings: - statement: TRAP-alpha mRNA is upregulated by GM-CSF - statement: Higher expression in proliferating vs quiescent cells - statement: Gene located on chromosome 6 - id: PMID:17380188 title: Simultaneous induction of the four subunits of the TRAP complex by ER stress accelerates ER degradation. findings: - statement: All four TRAP subunits induced by ER stress via XBP1/IRE1alpha pathway - statement: TRAP complex associates with ERAD substrates at late stage - statement: Preferential binding to misfolded proteins over correctly folded substrates - statement: TRAP involved in ERAD pathway, not just nascent polypeptide biosynthesis - id: PMID:22314232 title: Palmitoylated calnexin is a key component of the ribosome-translocon complex. findings: - statement: Palmitoylated calnexin associates with ribosome-translocon complex (RTC) including TRAP - statement: This supercomplex formation is essential for glycoprotein folding - id: PMID:29568061 title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. findings: - statement: Confirmed TRAP-alpha interaction with calnexin by proximity labeling - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: - statement: High-throughput proteomics confirming SSR1 interactions with calnexin and SEC61B - id: PMID:36697828 title: Visualization of translation and protein biogenesis at the ER membrane. findings: - statement: Near-atomic resolution cryo-ET structure of SEC61-TRAP-OSTA translocon complex - statement: TRAP present in both signal peptide and multipass translocon variants - statement: AlphaFold model of TRAP fits structural density - statement: TRAP makes specific interactions with SEC61 and OSTA within the translocon - id: Reactome:R-HSA-1791164 title: Expression of SSR1 (Trap alpha) findings: - statement: Basic gene expression pathway for SSR1 - id: file:human/SSR1/SSR1-deep-research-falcon.md title: Deep research review of SSR1 findings: - statement: TRAP-alpha is the alpha subunit of the ER-resident TRAP complex that stably associates with the Sec61 protein-conducting channel and the ribosome - statement: TRAP assists co-translational translocation of secretory and membrane proteins, especially those with weak or atypical signal peptides - statement: Cryo-EM structures show TRAP-alpha contains a prominent luminal domain positioned directly beneath the Sec61alpha channel exit and a long, diagonal transmembrane helix core_functions: - description: Core component of the ribosome-translocon complex facilitating co-translational translocation of nascent polypeptides molecular_function: id: GO:0005515 label: protein binding directly_involved_in: - id: GO:0006613 label: cotranslational protein targeting to membrane - id: GO:0036503 label: ERAD pathway locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:36697828 supporting_text: "near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) reveals specific interactions of TRAP with other translocon components" - reference_id: PMID:8050590 supporting_text: "The alpha-subunit of the TRAP complex (TRAP alpha) is a single-spanning membrane protein of the endoplasmic reticulum (ER) which is found in proximity of nascent polypeptide chains translocating across the membrane." proposed_new_terms: [] suggested_questions: - question: What is the precise mechanism by which TRAP-alpha recognizes and assists translocation of substrates with weak signal peptides? - question: Does TRAP-alpha have substrate specificity or does it function equivalently for all translocon-dependent substrates? - question: What is the functional significance of TRAP-alpha phosphorylation at Ser-268 during mitosis? suggested_experiments: - description: Structure-function studies with TRAP-alpha luminal domain mutants to determine residues critical for nascent chain interaction - description: Quantitative proteomics comparing translocation efficiency of defined substrates in TRAP-knockdown vs control cells - description: Investigation of TRAP-alpha post-translational modifications and their regulation during cell cycle or ER stress