id: Q9Y6X1 gene_symbol: SERP1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: SERP1 (stress-associated endoplasmic reticulum protein 1, also RAMP4, ribosome-attached/associated membrane protein 4) is a small (66 aa) single-pass endoplasmic reticulum membrane protein that associates with the Sec61 translocon. It is induced by ER stress and hypoxia and binds nascent membrane and secretory proteins during their translocation into the ER, protecting these still-unfolded substrates from degradation while ER stress persists and then facilitating their N-glycosylation after stress resolves, including modulating which N-glycosylation sites are used. Through these activities SERP1 contributes to the endoplasmic reticulum unfolded protein response and to the biogenesis and quality control of membrane proteins at the translocon. It physically associates with components of the Sec61 complex (SEC61A1, SEC61B) and calnexin. existing_annotations: - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: SERP1 acts at the ER (translocon) where it stabilizes nascent membrane proteins; the phylogenetic active-site assignment is correct. 2024 cryo-EM (PMID:38896445) directly shows RAMP4/SERP1 intercalated into the Sec61 lateral gate, confirming its translocon-associated site of action. action: ACCEPT reason: Core site of action; SERP1 is a translocon-associated ER membrane protein. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: Interacts with target proteins during their translocation into the lumen of the endoplasmic reticulum - reference_id: PMID:38896445 - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: SERP1 is stress-induced and acts during ER stress to protect nascent membrane proteins, placing it in the ER unfolded protein response; the phylogenetic assignment is well supported. action: ACCEPT reason: Core biological process; SERP1 (stress-associated ER protein) functions during ER stress to protect translocating substrates. supported_by: - reference_id: file:human/SERP1/SERP1-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 experimental and orthology evidence. action: ACCEPT reason: Correct core localization. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: Endoplasmic reticulum membrane - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: SERP1 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/SERP1/SERP1-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-pass membrane' - 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 SERP1 localization. supported_by: - reference_id: file:human/SERP1/SERP1-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 SERP1 interaction (TMEM79); 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/SERP1/SERP1-uniprot.txt supporting_text: 'Q9Y6X1; Q9BSE2: TMEM79' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI binary-interactome screen capturing SERP1 binding to a large set of membrane and secretory proteins; these are consistent with SERP1's translocon-substrate-stabilizing role but the bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Many partners are nascent membrane-protein substrates consistent with SERP1's function, but bare protein binding is uninformative per guidelines. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Q9Y6X1; Q9BY50: SEC11C' - 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 stronger evidence. action: ACCEPT reason: Correct core localization, redundant with IEA/TAS evidence. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-pass membrane' - 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 SERP1 localization. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-' - term: id: GO:0005881 label: cytoplasmic microtubule evidence_type: IDA original_reference_id: PMID:23264731 qualifier: located_in review: summary: The cited paper characterizes MTR120/KIAA1383, an unrelated ~120 kDa microtubule-associated protein, and contains no data on SERP1/RAMP4. SERP1 is a 66 aa single-pass ER membrane protein, for which a cytoplasmic-microtubule localization is biologically implausible. This annotation is a mis-attribution. action: REMOVE reason: The full text of PMID:23264731 is available and is entirely about MTR120/KIAA1383 with no mention of SERP1/RAMP4; the cytoplasmic-microtubule localization is inconsistent with SERP1's established ER membrane localization and topology. This is a demonstrable wrong-gene mis-attribution, not a second-guessing of supporting evidence. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-pass membrane' - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1791167 qualifier: located_in review: summary: Reactome curation of SERP1 ER membrane localization (SERP1/RAMP4 expression context). action: ACCEPT reason: Correct core localization; redundant with experimental/orthology evidence. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-pass membrane' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9609921 qualifier: located_in review: summary: Reactome cytosol annotation arising from a tail-anchored-protein (SGTA) pathway context; SERP1 is an ER membrane protein with a cytosol-facing portion, but cytosol is not its primary compartment. action: KEEP_AS_NON_CORE reason: The primary localization is the ER membrane; the cytosol annotation reflects a pathway context (TA-protein targeting) and the cytosol-facing topology rather than a core localization. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: 'Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9R2C1}; Single-pass membrane' - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: TAS original_reference_id: PMID:10601334 qualifier: located_in review: summary: The defining SERP1/RAMP4 study localizes the protein to the ER, where it acts during stress. action: ACCEPT reason: Core localization, from the primary characterization of SERP1. supported_by: - reference_id: PMID:10601334 supporting_text: stabilizes membrane proteins during stress and facilitates subsequent glycosylation - term: id: GO:0005840 label: ribosome evidence_type: TAS original_reference_id: PMID:10601334 qualifier: located_in review: summary: SERP1 is also named RAMP4 (ribosome-associated/attached membrane protein 4) for its association with ribosome-translocon junctions at the ER; the ribosome term is broad relative to this translocon-associated context. action: KEEP_AS_NON_CORE reason: Reflects the RAMP4 ribosome/translocon association, but the bare ribosome term is a coarse descriptor of its translocon-associated localization; the core compartment is the ER membrane. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: Interacts with SEC61B, SEC61A1 and the SEC61 complex - term: id: GO:0007009 label: plasma membrane organization evidence_type: TAS original_reference_id: PMID:10601334 qualifier: involved_in review: summary: By stabilizing nascent membrane proteins during stress, SERP1 indirectly influences the surface expression of membrane proteins; this is a downstream consequence rather than a core function. action: KEEP_AS_NON_CORE reason: Indirect, downstream effect of SERP1's translocon-substrate stabilization; not a core function. supported_by: - reference_id: PMID:10601334 supporting_text: stabilizes membrane proteins during stress - term: id: GO:0009101 label: glycoprotein biosynthetic process evidence_type: TAS original_reference_id: PMID:10601334 qualifier: involved_in review: summary: SERP1 facilitates N-glycosylation of its target proteins after termination of ER stress and may modulate which N-glycosylation sites are used; a real but modulatory/secondary role. action: KEEP_AS_NON_CORE reason: Supported by the primary study and UniProt, but a downstream/modulatory effect on glycosylation rather than the core stabilization function. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: May facilitate glycosylation of target proteins after termination of ER stress - term: id: GO:0036211 label: protein modification process evidence_type: TAS original_reference_id: PMID:10601334 qualifier: involved_in review: summary: Very general process term (parent of glycosylation), derived from SERP1's role in facilitating glycosylation of its targets. action: KEEP_AS_NON_CORE reason: Overly general; the more specific GO:0009101 (glycoprotein biosynthetic process) captures the relevant activity, and even that is secondary. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: May facilitate glycosylation of target proteins after termination of ER stress 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:10601334 title: Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and facilitates subsequent glycosylation. findings: - statement: SERP1/RAMP4 is an ER-stress-induced, translocon-associated ER membrane protein that stabilizes nascent membrane proteins during stress and facilitates their glycosylation after stress. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Defining characterization of SERP1/RAMP4; establishes the stress-induced translocon-associated stabilization and post-stress glycosylation roles. - id: PMID:23264731 title: MTR120/KIAA1383, a novel microtubule-associated protein, promotes microtubule stability and ensures cytokinesis. findings: - statement: Characterizes MTR120/KIAA1383, an unrelated ~120 kDa microtubule-associated protein; the full text contains no data on SERP1/RAMP4. reference_section_type: ABSTRACT reference_review: relevance: NONE correctness: WRONG_IDENTIFIER review_notes: Paper is entirely about MTR120/KIAA1383, not SERP1/RAMP4; the cytoplasmic-microtubule IDA annotation on SERP1 is a wrong-gene mis-attribution and is recommended for removal. - 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 (TMEM79), not relevant to SERP1'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 SERP1's translocon role but individually uninformative. - id: Reactome:R-HSA-1791167 title: Expression of SERP1 (RAMP4) findings: [] - id: Reactome:R-HSA-9609921 title: SGTA binds Tail-anchored protein findings: [] - id: file:human/SERP1/SERP1-uniprot.txt title: UniProt entry Q9Y6X1 (SERP1_HUMAN), stress-associated endoplasmic reticulum protein 1 / RAMP4 findings: - statement: Single-pass ER membrane protein 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:38896445 title: Structural analysis of the dynamic ribosome-translocon complex. findings: - statement: Cryo-EM of native ribosome-translocon complexes shows that a large proportion contain RAMP4 (SERP1) intercalated into the Sec61 lateral gate, widening the central pore and contributing to its hydrophilic interior; this places SERP1/RAMP4 as a structural, gating-modulating component of the Sec61 translocon. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Lewis, Zhong, Keenan, Hegde, eLife 2024; DOI 10.7554/eLife.95814). Direct structural evidence that RAMP4/SERP1 occupies the Sec61 lateral gate and widens the pore, supporting the translocon-associated, gating-modulating role. The Falcon report cited the bioRxiv preprint DOI (10.1101/2023.12.22.572959); this is the published eLife version. Not cached, so no verbatim supporting_text added to annotations. - id: PMID:31461934 title: A Dengue Virus Type 2 (DENV-2) NS4B-Interacting Host Factor, SERP1, Reduces DENV-2 Production by Suppressing Viral RNA Replication. findings: - statement: SERP1 was identified as a DENV-2 NS4B-interacting host factor; SERP1 is strongly induced (~34.5-fold) under DENV-2-induced ER stress, and SERP1 overexpression suppresses DENV-2 RNA replication and viral yield, consistent with a protective ER-stress-associated role. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Tian et al., Viruses 2019; DOI 10.3390/v11090787). SERP1-specific experimental study (interaction, induction, knockdown/knockout). Establishes ER-stress inducibility and an antiviral/proteostasis-protective context; does not by itself ground a new GO annotation beyond the existing UPR/ER terms. Not cached. - id: PMID:35419615 title: SERP1 reduces inchoate acute hepatic injury through regulation of endoplasmic reticulum stress via the GSK3beta/beta-catenin/TCF/LEF signaling pathway. findings: - statement: In acute hepatic injury models, SERP1 expression rises with ER stress, and SERP1 overexpression reduces ER-stress markers (GRP78/GRP94/CHOP), apoptosis, and inflammation, supporting a cytoprotective role during ER stress. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Cai et al., Mol Med Rep 2022; DOI 10.3892/mmr.2022.12709). SERP1-specific overexpression study in a liver-injury context; supports a protective ER-stress role but is a downstream/physiological readout rather than direct evidence for a core molecular function. Not cached. - id: PMID:32019826 title: A clearer picture of the ER translocon complex. findings: - statement: Review of the ER translocon; RAMP4/SERP1 is among the ribosome-associated membrane proteins recovered with Sec61-containing translocon fractions, supporting its translocon-associated localization. reference_section_type: OTHER reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Gemmer & Forster, J Cell Sci 2020; DOI 10.1242/jcs.231340). Authoritative translocon review providing family-level context for RAMP4/SERP1 association with the Sec61 translocon. Not cached. core_functions: - description: Stress-induced, Sec61-translocon-associated ER membrane protein that binds and stabilizes nascent membrane and secretory proteins during ER stress, protecting them from premature degradation. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: Protects unfolded target proteins against degradation during ER stress - reference_id: PMID:10601334 supporting_text: stabilizes membrane proteins during stress and facilitates subsequent glycosylation locations: - id: GO:0005789 label: endoplasmic reticulum membrane directly_involved_in: - id: GO:0030968 label: endoplasmic reticulum unfolded protein response - description: Facilitates N-glycosylation of its target proteins after termination of ER stress and may modulate the use of N-glycosylation sites, coupling membrane-protein stabilization to subsequent maturation. supported_by: - reference_id: file:human/SERP1/SERP1-uniprot.txt supporting_text: May facilitate glycosylation of target proteins after termination of ER stress locations: - id: GO:0005789 label: endoplasmic reticulum membrane proposed_new_terms: [] suggested_questions: - question: Does SERP1/RAMP4 protect nascent substrates by physically shielding them at the translocon, by recruiting chaperones such as calnexin, or by slowing translocation, and is this selective for particular substrate classes? - question: How does SERP1 modulate N-glycosylation site usage on its targets after ER stress resolves? suggested_experiments: - description: Site-specific proximity proteomics (e.g., split-BioID at the Sec61 translocon) under ER stress to define the SERP1-dependent nascent-substrate interactome and its dynamics through stress and recovery. - description: Glycoproteomic comparison of SERP1 wild-type versus knockout cells before and after ER stress to test the proposed stabilization and N-glycosylation-site-modulation functions on defined substrates.