id: P43308 gene_symbol: SSR2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- SSR2 encodes the beta subunit of the translocon-associated protein (TRAP) complex, also known as signal sequence receptor subunit beta (SSR-beta/TRAP-beta). TRAP is a heterotetrameric complex (SSR1/alpha, SSR2/beta, SSR3/gamma, SSR4/delta) that associates with the Sec61 translocon at the endoplasmic reticulum membrane. The complex assists in co-translational protein translocation, particularly for nascent polypeptides with weak or suboptimal signal peptides. SSR2/TRAP-beta is a type I single-pass membrane glycoprotein with its N-terminus facing the ER lumen, where it contributes to the lumenal crescent structure that contacts nascent chains exiting the Sec61 pore. The TRAP complex also coordinates with the oligosaccharyltransferase (OST) complex to facilitate N-glycosylation of nascent proteins. SSR2 was identified as a STING1 interactor in a yeast-two-hybrid screen (PMID:18724357), but the biological significance of this interaction is uncertain; it likely reflects proximity at the ER membrane rather than a dedicated immune-signaling function. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This IEA annotation is derived from InterPro domain mapping (IPR008856 TRAP_beta). SSR2/TRAP-beta is well-established as an ER-resident protein. The protein is part of the TRAP complex that associates with the Sec61 translocon at the ER membrane [file:human/SSR2/SSR2-deep-research-falcon.md]. action: ACCEPT reason: >- Accurate annotation. SSR2 is an integral ER membrane protein as part of the TRAP complex. The InterPro-based inference is consistent with extensive experimental evidence showing ER localization [PMID:7789174, PMID:36697828]. supported_by: - reference_id: PMID:7789174 supporting_text: "We have isolated a human cDNA clone homologous to the canine beta-signal sequence receptor gene, which codes for an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane." - reference_id: file:human/SSR2/SSR2-deep-research-falcon.md supporting_text: "[Deep research confirms] SSR2 encodes TRAP-beta (signal sequence receptor subunit beta) ... predominantly resides in the endoplasmic reticulum" - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: >- This IEA annotation is based on UniProt subcellular location vocabulary mapping. SSR2 is an integral ER membrane protein with a single transmembrane helix. UniProt records: "Endoplasmic reticulum membrane; Single-pass type I membrane protein." action: ACCEPT reason: >- Accurate and well-supported annotation. SSR2/TRAP-beta has type I topology (N lumen, C cytosol) with a single transmembrane helix embedded in the ER membrane [file:human/SSR2/SSR2-deep-research-falcon.md]. Cryo-EM structures confirm this localization [PMID:36697828]. 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" - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- This IEA annotation is derived from InterPro domain mapping. While correct that SSR2 is a membrane protein, this term is too general compared to the more specific GO:0005789 (endoplasmic reticulum membrane) annotation that is also present. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0005789 (endoplasmic reticulum membrane) is already annotated and is strictly more specific. GO:0016020 is redundant given that more precise localization information is captured by the ER-membrane term; best-practice curation flags such general terms as over-annotations when a specific child is present. supported_by: - reference_id: PMID:7789174 supporting_text: "which codes for an endoplasmic reticulum (ER) membrane protein" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18724357 review: summary: >- This IPI annotation is based on the interaction between SSR2/TRAP-beta and STING1, demonstrated by yeast two-hybrid screening and co-immunoprecipitation in PMID:18724357. The study identified SSR2 as a STING1 interactor and showed that TRAP-beta ablation reduced STING's ability to induce interferon-beta. action: MARK_AS_OVER_ANNOTATED reason: >- The evidence for this IPI record is the STING1 interaction (WITH Q86WV6, PMID:18724357, yeast-two-hybrid plus co-IP). The interaction is experimentally real but its biological significance is uncertain; the paper frames it as the translocon potentially influencing STING-mediated innate signalling, not as a core SSR2 function. Substituting GO:0106138 (Sec61 translocon complex binding) as the replacement term would swap in a different molecular partner unsupported by this IPI evidence record. MARK_AS_OVER_ANNOTATED is the appropriate disposition: protein binding is non-informative and this specific STING1 interaction is peripheral to SSR2's core role. GO:0106138 is retained in core_functions, supported by structural co-complex evidence (PMID:36697828). supported_by: - reference_id: PMID:18724357 supporting_text: "we screened an IFN-induced, human fibroblast yeast two-hybrid cDNA library using STING (amino acids 173-379) as a bait and repeatedly isolated Ssr2/TRAPbeta, a member of the TRAP complex comprising four subunits (alpha-delta) that facilitates translocation of proteins into the ER following translation" - reference_id: PMID:18724357 supporting_text: "we confirmed that TRAPbeta can indeed associate with endogenous STING in HEK 293 cells following co-immunoprecipitation experiments" - term: id: GO:0106138 label: Sec61 translocon complex binding evidence_type: IDA original_reference_id: PMID:36697828 review: summary: >- NEW annotation proposed to capture the direct physical association of SSR2/TRAP-beta with the Sec61 translocon, as demonstrated by cryo-electron tomography showing the near-complete atomic model of the SEC61-TRAP-OSTA complex. TRAP stably associates with Sec61 at the ER membrane. action: NEW reason: >- The cryo-ET study (PMID:36697828) directly visualizes the TRAP complex in stable association with Sec61 in native ER membranes, providing structural IDA-level evidence for Sec61 translocon complex binding. This is the core MF of SSR2 and should be annotated directly rather than inferred by remapping the STING1 IPI record. The co-IP data in PMID:18724357 (Sec61beta co-IP) provides additional biochemical support. supported_by: - reference_id: PMID:36697828 supporting_text: "The 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:0005789 label: endoplasmic reticulum membrane evidence_type: NAS original_reference_id: PMID:36697828 review: summary: >- This NAS annotation is based on Gemmer et al. (2023), which used cryo-electron tomography to visualize the native ER translocon including the TRAP complex. The study provides near-complete atomic models of the SEC61-TRAP-OSTA complex at the ER membrane. action: ACCEPT reason: >- This is an accurate annotation supported by high-resolution structural data. The cryo-ET study directly visualizes SSR2/TRAP-beta as an integral component of the ER membrane translocon complex [PMID:36697828]. supported_by: - reference_id: PMID:36697828 supporting_text: "The 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:0031204 label: post-translational protein targeting to membrane, translocation evidence_type: NAS original_reference_id: PMID:36697828 review: summary: >- This NAS annotation suggests SSR2/TRAP-beta is involved in post-translational protein translocation. However, the TRAP complex is primarily associated with co-translational translocation, assisting the Sec61 translocon during ribosome- associated protein synthesis and membrane insertion. action: REMOVE reason: >- GO:0031204 captures post-translational protein targeting, but the TRAP complex acts co-translationally (ribosome-bound Sec61 complexes). The correct sub-pathway term, GO:0006613 (cotranslational protein targeting to membrane), is already independently annotated from PMID:7789174. MODIFY to a term already present would produce a duplicate; REMOVE is the cleaner disposition for the incorrectly assigned sub-pathway term. supported_by: - reference_id: PMID:36697828 supporting_text: "distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass transmembrane proteins with the translocon-associated protein complex (TRAP) present in both" - reference_id: file:human/SSR2/SSR2-deep-research-falcon.md supporting_text: "[Deep research confirms] TRAP is a heterotetramer of SSR1 (alpha), SSR2 (beta), SSR3 (gamma), SSR4 (delta) ... co-translational protein translocation" - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:7789174 review: summary: >- This TAS annotation is based on the original cloning paper by Chinen et al. (1995) which identified SSR2 as encoding an ER membrane protein. The paper describes isolation of the human beta-signal sequence receptor gene. action: ACCEPT reason: >- Accurate annotation with appropriate primary literature support. The paper explicitly describes SSR2 as encoding "an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane." supported_by: - reference_id: PMID:7789174 supporting_text: "We have isolated a human cDNA clone homologous to the canine beta-signal sequence receptor gene, which codes for an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane." - term: id: GO:0006613 label: cotranslational protein targeting to membrane evidence_type: TAS original_reference_id: PMID:7789174 review: summary: >- This TAS annotation captures the core function of SSR2/TRAP-beta in co-translational protein translocation. The TRAP complex associates with ribosome-Sec61 complexes and facilitates membrane targeting of nascent polypeptides, particularly those with weak or suboptimal signal peptides. action: ACCEPT reason: >- This is a core function annotation. SSR2 as part of the TRAP complex is directly involved in co-translational protein translocation at the ER membrane. Recent cryo-EM studies confirm that TRAP is consistently present in the co-translational translocon and modulates Sec61 function for challenging substrates [PMID:36697828; file:human/SSR2/SSR2-deep-research-falcon.md]. supported_by: - reference_id: PMID:7789174 supporting_text: "which codes for an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane" additional_reference_ids: - PMID:36697828 - term: id: GO:0016020 label: membrane evidence_type: TAS original_reference_id: PMID:7789174 review: summary: >- This TAS annotation based on PMID:7789174 indicates SSR2 is a membrane protein. This is accurate but less specific than GO:0005789 (ER membrane) which is also annotated from the same reference. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0005789 (endoplasmic reticulum membrane) is annotated from the same reference and is more informative. GO:0016020 is a redundant parent term; retaining only the specific child term is consistent with curation best practice. supported_by: - reference_id: PMID:7789174 supporting_text: "which codes for an endoplasmic reticulum (ER) membrane protein" references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms 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: PMID:18724357 title: STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. findings: - statement: Yeast two-hybrid screening identified SSR2/TRAP-beta as a STING1 interacting protein supporting_text: "we screened an IFN-induced, human fibroblast yeast two-hybrid cDNA library using STING (amino acids 173-379) as a bait and repeatedly isolated Ssr2/TRAPbeta" - statement: Co-immunoprecipitation confirmed TRAP-beta association with endogenous STING supporting_text: "we confirmed that TRAPbeta can indeed associate with endogenous STING in HEK 293 cells following co-immunoprecipitation experiments" - statement: TRAP-beta ablation reduced STING-mediated interferon-beta induction supporting_text: "loss of TRAPbeta or SEC61beta reduced STING's, ability to induce an IFNbeta promoter driving luciferase" - id: PMID:36697828 title: Visualization of translation and protein biogenesis at the ER membrane. findings: - statement: Cryo-electron tomography visualization of native ER translocon complexes supporting_text: "Here we use cryo-electron tomography, extensive classification and molecular modelling to capture snapshots of mRNA translation and protein maturation at the ER membrane" - statement: Near-complete atomic model of SEC61-TRAP-OSTA complex supporting_text: "The near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA)" - statement: TRAP present in both signal peptide and multipass translocon variants supporting_text: "distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass transmembrane proteins with the translocon-associated protein complex (TRAP) present in both" - id: PMID:7789174 title: Isolation and mapping of the human beta-signal sequence receptor gene (SSR2). findings: - statement: Original cloning of human SSR2 cDNA supporting_text: "We have isolated a human cDNA clone homologous to the canine beta-signal sequence receptor gene" - statement: Identified SSR2 as encoding ER membrane protein involved in translocation supporting_text: "which codes for an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane" - statement: Mapped SSR2 to chromosome 1q21-q23 supporting_text: "We also localized the human beta-signal sequence receptor gene (SSR2) to chromosome bands 1q21-->q23" - id: file:human/SSR2/SSR2-deep-research-falcon.md title: Deep research summary for SSR2/TRAP-beta findings: - statement: Comprehensive review of TRAP complex structure and function from recent literature - statement: TRAP is a heterotetramer (alpha, beta, gamma, delta subunits) - statement: TRAP-beta has type I topology with single transmembrane helix - statement: TRAP modulates Sec61 lateral gate for weak signal peptides core_functions: - description: >- SSR2/TRAP-beta is a component of the TRAP complex that associates with the Sec61 translocon during co-translational protein translocation. The complex assists in membrane targeting and insertion of nascent polypeptides with weak or suboptimal signal peptides [PMID:7789174; PMID:36697828]. molecular_function: id: GO:0106138 label: Sec61 translocon complex binding directly_involved_in: - id: GO:0006613 label: cotranslational protein targeting to membrane locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:7789174 supporting_text: "which codes for an endoplasmic reticulum (ER) membrane protein associated with protein translocation across the ER membrane" - reference_id: PMID:36697828 supporting_text: "The 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." proposed_new_terms: - proposed_name: TRAP complex proposed_definition: >- A heterotetrameric protein complex composed of TRAP-alpha (SSR1), TRAP-beta (SSR2), TRAP-gamma (SSR3), and TRAP-delta (SSR4) subunits that associates with the Sec61 translocon at the endoplasmic reticulum membrane. The TRAP complex facilitates co-translational protein translocation, particularly for substrates with weak or suboptimal signal peptides. justification: >- There is currently no specific GO term for the translocon-associated protein (TRAP) complex. This heterotetrameric complex (SSR1-4/TRAP-alpha,beta,gamma,delta) is distinct from the Sec61 translocon core and functions as a co-factor for protein translocation. A dedicated cellular component term would improve annotation precision for all TRAP subunit genes. Note that ComplexPortal CPX-8024 ("Translocon-associated protein complex") already captures this complex and is cited in the UniProt record; the GO request should reference CPX-8024 as supporting evidence for the complex's existence and composition. suggested_questions: - question: >- What is the precise mechanism by which the TRAP complex modulates Sec61 lateral gate dynamics to facilitate translocation of weak signal peptide substrates? Recent structural and MD studies suggest TRAP influences gate conformations but the detailed mechanism remains incompletely characterized. - question: >- What is the functional significance of the SSR2/TRAP-beta interaction with STING1? Is this interaction related to TRAP's role in protein translocation or does it represent a distinct function in innate immune signaling? The STING1 interaction was identified in a focused study on innate immunity, but whether this represents a core or peripheral function of SSR2 is unclear.