id: Q8N6R1 gene_symbol: SERP2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: SERP2 (stress-associated endoplasmic reticulum protein 2, also RAMP4-2, ribosome-associated membrane protein RAMP4-2) is a small (65 aa) single-pass endoplasmic reticulum membrane protein of the RAMP4 family and a paralog of SERP1/RAMP4. Like SERP1, it associates with the Sec61 translocon and binds nascent membrane and secretory proteins during their translocation into the ER, protecting these still-unfolded substrates from degradation during ER stress and facilitating their N-glycosylation after stress resolves, including modulating which N-glycosylation sites are used. Through these activities SERP2 contributes to the endoplasmic reticulum unfolded protein response and to membrane-protein biogenesis at the translocon. It physically associates with components of the Sec61 complex (SEC61A1, SEC61B) and calnexin. Its function is established largely by orthology and paralogy, and it is less experimentally characterized than SERP1. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: SERP2 acts at the ER (translocon) where, like its SERP1 paralog, it stabilizes nascent membrane proteins; the phylogenetic active-site assignment is correct. action: ACCEPT reason: Core site of action; SERP2 is a translocon-associated ER membrane protein. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: Interacts with target proteins during their translocation into the lumen of the endoplasmic reticulum - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: SERP2 is a stress-associated ER protein that acts during ER stress to protect nascent membrane proteins, placing it in the ER unfolded protein response. action: ACCEPT reason: Core biological process; SERP2 functions during ER stress to protect translocating substrates. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: Protects unfolded target proteins against degradation during ER stress - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: located_in review: summary: InterPro-based ER localization, consistent with orthology and phylogenetic evidence. action: ACCEPT reason: Correct core localization. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: Interacts with SEC61B, SEC61A1 and the SEC61 complex - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: SERP2 is a single-pass ER membrane protein; the subcellular-location-based annotation is correct. action: ACCEPT reason: Core localization, consistent with the single-pass ER membrane topology. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-' - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Generic membrane localization, a parent of the more informative ER membrane term. action: KEEP_AS_NON_CORE reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SERP2 localization. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Proteome-scale interactome capture of a SERP2 interaction; a real interaction but the bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome capture; bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Q8N6R1; Q8N6L0' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI binary-interactome screen capturing SERP2 binding to a large set of membrane and secretory proteins; consistent with a translocon-substrate-stabilizing role but the bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Many partners are membrane-protein substrates consistent with SERP2's function, but bare protein binding is uninformative per guidelines. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Q8N6R1; Q13520: AQP6' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity transfer of ER membrane localization from the mouse ortholog; consistent with the RAMP4-family identity. action: ACCEPT reason: Correct core localization, redundant with IEA evidence. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-' - term: id: GO:0016020 label: membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity transfer of generic membrane localization; a parent of ER membrane. action: KEEP_AS_NON_CORE reason: Correct but uninformative; the specific GO:0005789 (ER membrane) better captures SERP2 localization. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: 'Membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-' references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms 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 findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of a bare protein binding annotation, not relevant to SERP2's core function. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: HuRI binary-interactome map; source of many bare protein binding annotations, largely with membrane/secretory proteins consistent with SERP2's translocon role but individually uninformative. - id: file:human/SERP2/SERP2-uniprot.txt title: UniProt entry Q8N6R1 (SERP2_HUMAN), stress-associated endoplasmic reticulum protein 2 / RAMP4-2 findings: - statement: Single-pass ER membrane protein of the RAMP4 family (SERP1 paralog) that interacts with target proteins during ER translocation, protects unfolded targets against degradation during ER stress, and facilitates their glycosylation after stress; interacts with the SEC61 complex and calnexin. reference_section_type: OTHER - id: PMID:30733280 title: The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. findings: - statement: RAMP4-2 (= SERP2; UniProt AltName "Ribosome-associated membrane protein RAMP4-2") is a tail-anchored ER membrane protein experimentally shown to be a substrate for intramembrane proteolysis; among the tail-anchored candidates tested it was efficiently cleaved by SPPL2c (and also by SPP), implicating SERP2 in regulated ER-membrane proteostasis/turnover. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Niemeyer et al., EMBO Rep 2019; DOI 10.15252/embr.201846449). Direct experimental evidence that RAMP4-2 (=SERP2 per UniProt AltName) is a tail-anchored ER protein and an SPPL2c/SPP intramembrane-protease substrate. The paper's primary focus is SPPL2c/phospholamban; the cached text was not available to anchor a verbatim supporting_text, so reference id only is added (no new GO annotation asserted). - id: PMID:37261541 title: The transmembrane domain of Frey1 harbors a transplantable inhibitory motif for intramembrane proteases. findings: - statement: Uses HA-RAMP4-2 (=SERP2) cleavage as the readout substrate for SPPL2c activity, corroborating that RAMP4-2/SERP2 is a tail-anchored ER substrate of the SPPL2c intramembrane protease. reference_section_type: OTHER reference_review: relevance: LOW correctness: VERIFIED review_notes: PubMed-verified (Contreras, Bazan, Mentrup, Cell Mol Life Sci 2023; DOI 10.1007/s00018-023-04823-7). RAMP4-2/SERP2 is used as a biochemical tool substrate for SPPL2c regulation rather than studied for its own function; supporting/contextual. Not cached. - id: PMID:38787756 title: RAMPing up knowledge of the translocon. findings: - statement: eLife Insight on cryo-EM of ribosome-translocon complexes; RAMP4-family proteins localize at the Sec61 lateral gate and are proposed to act as a dynamic, gating-modulating component of the translocon, providing family-level context for the RAMP4-family member SERP2. reference_section_type: OTHER reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Vismpas & Forster, eLife 2024; DOI 10.7554/eLife.98548). Editorial/Insight discussing RAMP4 at the Sec61 lateral gate; the structural data concern RAMP4/SERP1, so this is family-level inference for SERP2, not SERP2-specific evidence. Not cached. - id: PMID:32019826 title: A clearer picture of the ER translocon complex. findings: - statement: Review of the ER translocon; the RAMP4 family is among ribosome-associated membrane proteins recovered with Sec61 translocon fractions, supporting translocon-associated localization for the RAMP4-family member SERP2 by family context. reference_section_type: OTHER reference_review: relevance: LOW correctness: VERIFIED review_notes: PubMed-verified (Gemmer & Forster, J Cell Sci 2020; DOI 10.1242/jcs.231340). Family-level/background context for the RAMP4 family; not SERP2-specific. Not cached. core_functions: - description: Sec61-translocon-associated ER membrane protein (SERP1/RAMP4 paralog) that binds and stabilizes nascent membrane and secretory proteins during ER stress, protecting them from premature degradation, and contributes to the ER unfolded protein response. supported_by: - reference_id: file:human/SERP2/SERP2-uniprot.txt supporting_text: Protects unfolded target proteins against degradation during ER stress locations: - id: GO:0005789 label: endoplasmic reticulum membrane directly_involved_in: - id: GO:0030968 label: endoplasmic reticulum unfolded protein response proposed_new_terms: [] suggested_questions: - question: Is SERP2/RAMP4-2 functionally redundant with SERP1/RAMP4, or does it have distinct substrate preferences, tissue expression, or stress-response behavior? - question: Which nascent membrane-protein substrates depend on SERP2 for stabilization or correct N-glycosylation during ER stress? suggested_experiments: - description: Generate SERP2 single and SERP1/SERP2 double knockouts and assess membrane-protein stability, surface expression, and glycosylation under ER stress to test redundancy with SERP1. - description: Proximity proteomics of SERP2 at the Sec61 translocon under basal and ER-stress conditions to define its substrate interactome and compare it with SERP1's.