{"gene":"SRPRB","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1986,"finding":"The SRP receptor is a heterodimer composed of a 69-kD alpha subunit (SR alpha) and a 30-kD beta subunit (SR beta/SRPRB). SR beta forms a tight complex with SR alpha in detergent solution, stable to high salt, and both subunits are present in the ER membrane in equimolar amounts and co-fractionate in constant stoichiometry.","method":"SRP-Sepharose affinity chromatography, immunoprecipitation with subunit-specific antibodies, sucrose gradient fractionation of rough and smooth liver microsomes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunoprecipitation, affinity purification, quantitative fractionation; foundational study replicated by multiple subsequent labs","pmids":["3021779"],"is_preprint":false},{"year":1993,"finding":"SR beta (SRPRB) binds GTP specifically. The SR alpha/SR beta receptor complex stimulates GTP binding to and GTP hydrolysis by SRP54, proposing a cascade of three directly interacting GTPases (SRP54, SR alpha, SR beta) that regulates protein targeting to the ER.","method":"GTP binding and GTPase assays in vitro with purified SRP and SRP receptor components; GTP hydrolysis measurements","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro GTPase and GTP-binding assays with purified components; independently referenced and replicated across multiple papers in corpus","pmids":["8247130","8299417"],"is_preprint":false},{"year":1995,"finding":"SR beta (SRPRB) is an integral transmembrane protein and a member of the GTPase superfamily, distantly related to ARF and Sar1, that anchors SR alpha to the ER membrane. UV cross-linking confirmed SR beta binds GTP specifically. SR alpha is peripherally associated with the ER membrane and requires SR beta for membrane attachment. SR alpha is required for the interaction of SRP with the SR complex.","method":"Molecular cloning and cDNA sequencing of SR beta; UV cross-linking GTP-binding assay; proteolytic digestion experiments to determine membrane topology; biochemical fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted GTP binding, molecular cloning with domain analysis, proteolytic protection, multiple orthogonal methods in single study","pmids":["7844142"],"is_preprint":false},{"year":1995,"finding":"The amino-terminal 140 residues of SR alpha constitute a membrane-binding domain that forms a protease-resistant folding unit and is the major site of tight binding with SR beta (SRPRB), indicating SR beta plays a role in the membrane assembly of SR alpha. SR alpha is not integrated into the ER membrane but is peripherally associated.","method":"Deletion mutagenesis of SR alpha, cell-free translation, microsome binding assays, alkaline carbonate extraction supplemented with 1 M NaSCN, proteolytic protection assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple biochemical assays in single study; mechanistic conclusion about SR beta binding domain confirmed","pmids":["7797564"],"is_preprint":false},{"year":1989,"finding":"Assembly of SR alpha onto the ER membrane occurs via a two-step mechanism (targeting to ER, then anchoring on the cytoplasmic face) that is distinct from SRP-dependent targeting. Both anchoring and translocation activity could be reconstituted in vitro, demonstrating functional ER membrane assembly of SR alpha that restores translocation activity.","method":"Cell-free reconstitution assay for SR alpha membrane assembly; N-ethylmaleimide-inactivated ER microsomes used to assess anchoring and translocation activity independently","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with functional readout, single lab, two orthogonal assays (anchoring + translocation)","pmids":["2537835"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of SR beta (SRPRB)-GTP in complex with the interaction domain of SR alpha at 1.7 Å resolution revealed that the binding interface overlaps largely with the switch 1 region of SR beta. Biochemical data showed that eukaryotic SR is a conditional (not obligate) heterodimer, and that the GTP/GDP switch cycle of SR beta functions as a regulatory switch for receptor dimerization.","method":"X-ray crystallography at 1.7 Å; supporting biochemical binding assays to test conditional heterodimer formation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus biochemical validation of conditional dimerization; rigorous single study with orthogonal structural and biochemical methods","pmids":["12654246"],"is_preprint":false},{"year":2023,"finding":"SR beta (SRPRB) is required for assembly of the N-glycosylation-competent translocon at the ER. Guanine analog chemical probes or mutation of the SR beta GTP-binding site caused an N-glycosylation-deficient phenotype without altering the SR alpha/SR beta association, but both approaches reduced the association of SR beta with the oligosaccharyltransferase (OST) complex, revealing a previously unrecognized function of SR beta in coordinating ER translation with N-glycosylation.","method":"High-throughput screening of guanine analog chemical probes; GTP-binding site mutagenesis; co-immunoprecipitation of SR beta with OST complex; N-glycosylation functional assays; CRISPR/Cas9 SRPRB knockout cell lines","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of active site + chemical probe + co-IP of OST complex + functional glycosylation assay + KO cell lines; multiple orthogonal methods in single study","pmids":["36921042"],"is_preprint":false},{"year":2023,"finding":"CRISPR/Cas9-mediated knockout of SRPRB caused profound destabilization of SRA (SR alpha), demonstrating that SR beta is required for SR alpha protein stability. SR double-knockout (SRPRB KO + siRNA SRPRA) cells were viable and showed that steady-state mRNA localization to the ER is largely SR-independent.","method":"CRISPR/Cas9 SRPRB knockout; siRNA silencing; cell fractionation; deep sequencing of ER-associated and cytosolic mRNAs; 4-thiouridine pulse-labeling/4SU-seq","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional and molecular readout (SR alpha destabilization), validated by orthogonal sequencing approach; single lab but multiple methods","pmids":["37643813"],"is_preprint":false},{"year":2006,"finding":"Ectopic expression of APMCF1 (SRPRB) in HHCC hepatocellular carcinoma cells (which lack endogenous APMCF1) inhibited cell growth and induced G1 cell cycle arrest associated with up-regulation of p21 and down-regulation of TIMP3, as assessed by cell cycle gene chip analysis. Conversely, RNAi-mediated knockdown of APMCF1 in HepG2 cells promoted cell growth.","method":"Liposome-mediated transfection for overexpression; RNAi knockdown; cell cycle gene chip analysis; growth assays","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression/knockdown with gene chip downstream readout but no direct mechanistic pathway validation; limited controls described in abstract","pmids":["17080297"],"is_preprint":false},{"year":2009,"finding":"APMCF1 (SRPRB) protein is localized to the cytoplasm of COS-7 cells when expressed as an EGFP fusion protein.","method":"Transient transfection of pEGFP-APMCF1 fusion construct in COS-7 cells; fluorescence microscopy","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment by fluorescence microscopy, single lab, no functional consequence directly linked to localization in this study","pmids":["19664239"],"is_preprint":false},{"year":2026,"finding":"Cardiac-specific overexpression of Srprb in pressure-overload heart failure mice exacerbated ventricular remodeling, structural/electrical abnormalities, and ventricular arrhythmia incidence, while Srprb knockdown improved these parameters. Mechanistically, Srprb promoted arrhythmia vulnerability by activating endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB signaling pathway. In vitro, Srprb modulation regulated angiotensin II-induced cardiomyocyte hypertrophy and TGF-β-induced fibroblast fibrosis.","method":"Adeno-associated virus-mediated cardiac-specific overexpression/knockdown in mice; aortic banding pressure-overload model; echocardiography; ECG; in vivo electrophysiology; adenovirus transfection of primary neonatal cardiomyocytes and fibroblasts; pathway inhibitor experiments; molecular and pathological analyses","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with functional cardiac phenotype, pathway inhibitor mechanistic confirmation, in vitro cellular validation; single lab, multiple orthogonal methods","pmids":["41568549"],"is_preprint":false},{"year":2026,"finding":"Knockdown of SRPRB in TNBC cell lines significantly inhibited proliferation, migration, and invasion, induced cell apoptosis, and suppressed the WNT signaling pathway as measured by expression of key WNT pathway regulatory proteins.","method":"siRNA/shRNA knockdown; CCK-8 and colony formation assays; Transwell and wound healing assays; flow cytometry; Hoechst staining; Western blot for WNT pathway proteins","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with multiple cellular readouts, WNT pathway association inferred from Western blot protein levels without direct epistasis or rescue experiments","pmids":["41875940"],"is_preprint":false}],"current_model":"SRPRB (SR beta) is an integral ER membrane GTPase that anchors SR alpha to the ER membrane, forms a conditional heterodimer with SR alpha regulated by its GTP/GDP switch cycle (as revealed by a 1.7 Å crystal structure), stimulates GTP binding and hydrolysis by SRP54 as part of a three-GTPase cascade driving cotranslational protein targeting to the ER, and additionally recruits the oligosaccharyltransferase complex to coordinate N-glycosylation of translocating proteins; loss of SRPRB destabilizes SR alpha and, beyond its canonical SRP receptor role, SRPRB overexpression activates ER stress and the TLR4/CaMKII/NF-κB pathway to promote cardiac hypertrophy, fibrosis, and arrhythmia."},"narrative":{"mechanistic_narrative":"SRPRB (SR beta) is the integral ER membrane GTPase subunit of the heterodimeric signal recognition particle (SRP) receptor, which mediates cotranslational targeting of secretory and membrane proteins to the ER [PMID:3021779, PMID:8247130, PMID:8299417]. SRPRB anchors the peripherally associated SR alpha subunit to the ER membrane through a tight interaction with the amino-terminal membrane-binding domain of SR alpha, and is required for SR alpha membrane assembly and protein stability [PMID:7844142, PMID:7797564, PMID:37643813]. As a member of the GTPase superfamily, SRPRB binds GTP specifically, and together with SR alpha stimulates GTP binding and hydrolysis by SRP54 in a three-GTPase cascade that drives protein targeting [PMID:8247130, PMID:8299417, PMID:7844142]. A 1.7 Å crystal structure of SRPRB-GTP bound to the SR alpha interaction domain showed that the binding interface overlaps the switch 1 region, establishing eukaryotic SR as a conditional heterodimer whose dimerization is governed by the SRPRB GTP/GDP switch cycle [PMID:12654246]. Beyond targeting, the GTP-binding activity of SRPRB is required to recruit the oligosaccharyltransferase (OST) complex and assemble an N-glycosylation-competent translocon, coordinating ER translation with N-glycosylation [PMID:36921042]. In the heart, cardiac-specific overexpression of Srprb exacerbates ventricular remodeling and arrhythmia by activating ER stress and TLR4/CaMKII/NF-κB signaling [PMID:41568549].","teleology":[{"year":1986,"claim":"Established that the SRP receptor is not a single protein but a tight, stoichiometric heterodimer, defining SR beta/SRPRB as an obligate partner of SR alpha at the ER membrane.","evidence":"SRP-Sepharose affinity chromatography, reciprocal immunoprecipitation, and sucrose gradient fractionation of liver microsomes","pmids":["3021779"],"confidence":"High","gaps":["Did not define which subunit carries enzymatic/GTPase activity","Membrane topology of each subunit unresolved"]},{"year":1993,"claim":"Identified SR beta as a GTP-binding protein and placed it within a three-GTPase cascade, answering how the receptor regulates SRP54 during targeting.","evidence":"In vitro GTP-binding and GTPase assays with purified SRP and SRP receptor components","pmids":["8247130","8299417"],"confidence":"High","gaps":["Structural basis of GTP-dependent regulation not resolved","Order and kinetics of the GTPase switches not fully defined"]},{"year":1995,"claim":"Resolved the membrane architecture of the receptor by cloning SR beta as an integral transmembrane GTPase that anchors the peripheral SR alpha, defining the basis of receptor assembly.","evidence":"cDNA cloning and domain analysis, UV cross-linking GTP-binding assay, proteolytic protection topology, and biochemical fractionation; deletion mutagenesis localizing the SR alpha membrane-binding domain","pmids":["7844142","7797564"],"confidence":"High","gaps":["Atomic-level interface between SR alpha and SR beta not yet defined","Regulatory role of the GTP/GDP cycle in dimerization not established"]},{"year":2003,"claim":"Provided the structural mechanism for receptor dimerization, showing SR is a conditional heterodimer controlled by the SR beta nucleotide state.","evidence":"1.7 Å X-ray crystal structure of SR beta-GTP bound to the SR alpha interaction domain with supporting biochemical binding assays","pmids":["12654246"],"confidence":"High","gaps":["Did not capture the full assembled receptor with membrane context","GDP-bound and apo states not structurally compared in same study"]},{"year":2023,"claim":"Extended SRPRB function beyond targeting by showing its GTP-binding activity recruits the OST complex to build an N-glycosylation-competent translocon.","evidence":"Guanine analog chemical probes, GTP-binding site mutagenesis, co-IP of SR beta with OST complex, N-glycosylation assays, and CRISPR/Cas9 knockout cells","pmids":["36921042"],"confidence":"High","gaps":["Direct physical contacts between SRPRB and specific OST subunits not mapped","Whether OST recruitment is concurrent with or sequential to targeting unresolved"]},{"year":2023,"claim":"Defined SRPRB as a determinant of SR alpha protein stability and tested the requirement of the receptor for ER mRNA localization.","evidence":"CRISPR/Cas9 SRPRB knockout plus siRNA double-knockout, cell fractionation, and 4SU-seq deep sequencing of ER-associated mRNAs","pmids":["37643813"],"confidence":"High","gaps":["Mechanism of SR alpha destabilization upon SRPRB loss not defined","Viability of double-knockout implies redundant targeting pathways not identified"]},{"year":2026,"claim":"Linked SRPRB dosage to cardiac pathology, showing overexpression drives arrhythmia and remodeling through ER stress and TLR4/CaMKII/NF-κB signaling.","evidence":"AAV cardiac-specific overexpression/knockdown in pressure-overload mice with echocardiography, ECG, in vivo electrophysiology, and pathway inhibitor experiments in primary cardiomyocytes and fibroblasts","pmids":["41568549"],"confidence":"Medium","gaps":["How a canonical SRP receptor subunit engages TLR4/CaMKII/NF-κB is mechanistically unexplained","Whether the phenotype depends on SRPRB GTPase/targeting function not tested"]},{"year":2026,"claim":"Associated SRPRB with cancer cell proliferation and migration phenotypes in TNBC, implicating WNT signaling.","evidence":"siRNA/shRNA knockdown with proliferation, migration, invasion, apoptosis assays and Western blot of WNT pathway proteins","pmids":["41875940"],"confidence":"Low","gaps":["WNT pathway link inferred from protein levels without epistasis or rescue","Single-lab knockdown without orthogonal validation or in vivo support"]},{"year":null,"claim":"It remains unclear how the canonical ER-membrane SRP-receptor GTPase function of SRPRB mechanistically connects to its reported roles in cell proliferation, cardiac remodeling, and WNT/NF-κB signaling.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experiments distinguish targeting-dependent from targeting-independent disease functions","Cytoplasmic localization reports conflict with established integral ER membrane topology","Direct effectors connecting SRPRB to NF-κB or WNT not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,6]}],"complexes":["SRP receptor (SR alpha/SR beta heterodimer)"],"partners":["SRPRA","SRP54","OST COMPLEX"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5M8","full_name":"Signal recognition particle receptor subunit beta","aliases":["Protein APMCF1"],"length_aa":271,"mass_kda":29.7,"function":"Component of the signal recognition particle (SRP) complex receptor (SR) (By similarity). Ensures, in conjunction with the SRP complex, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system (By similarity). May mediate the membrane association of SR (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y5M8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRPRB","classification":"Common Essential","n_dependent_lines":916,"n_total_lines":1208,"dependency_fraction":0.7582781456953642},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000144867","cell_line_id":"CID001599","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"SRPRA","stoichiometry":10.0},{"gene":"DAD1","stoichiometry":4.0},{"gene":"SRP19","stoichiometry":4.0},{"gene":"SRP68","stoichiometry":4.0},{"gene":"SRP72","stoichiometry":4.0},{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CDS2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001599","total_profiled":1310},"omim":[{"mim_id":"616883","title":"SRP RECEPTOR SUBUNIT, BETA; SRPRB","url":"https://www.omim.org/entry/616883"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRPRB"},"hgnc":{"alias_symbol":["APMCF1","SR-beta"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5M8","domains":[{"cath_id":"3.40.50.300","chopping":"64-210_228-271","consensus_level":"high","plddt":93.7741,"start":64,"end":271},{"cath_id":"1.20.5","chopping":"26-61","consensus_level":"high","plddt":80.9833,"start":26,"end":61}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5M8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5M8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5M8-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRPRB","jax_strain_url":"https://www.jax.org/strain/search?query=SRPRB"},"sequence":{"accession":"Q9Y5M8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5M8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5M8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5M8"}},"corpus_meta":[{"pmid":"8247130","id":"PMC_8247130","title":"GTP 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SR beta forms a tight complex with SR alpha in detergent solution, stable to high salt, and both subunits are present in the ER membrane in equimolar amounts and co-fractionate in constant stoichiometry.\",\n      \"method\": \"SRP-Sepharose affinity chromatography, immunoprecipitation with subunit-specific antibodies, sucrose gradient fractionation of rough and smooth liver microsomes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunoprecipitation, affinity purification, quantitative fractionation; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"3021779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"SR beta (SRPRB) binds GTP specifically. The SR alpha/SR beta receptor complex stimulates GTP binding to and GTP hydrolysis by SRP54, proposing a cascade of three directly interacting GTPases (SRP54, SR alpha, SR beta) that regulates protein targeting to the ER.\",\n      \"method\": \"GTP binding and GTPase assays in vitro with purified SRP and SRP receptor components; GTP hydrolysis measurements\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro GTPase and GTP-binding assays with purified components; independently referenced and replicated across multiple papers in corpus\",\n      \"pmids\": [\"8247130\", \"8299417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SR beta (SRPRB) is an integral transmembrane protein and a member of the GTPase superfamily, distantly related to ARF and Sar1, that anchors SR alpha to the ER membrane. UV cross-linking confirmed SR beta binds GTP specifically. SR alpha is peripherally associated with the ER membrane and requires SR beta for membrane attachment. SR alpha is required for the interaction of SRP with the SR complex.\",\n      \"method\": \"Molecular cloning and cDNA sequencing of SR beta; UV cross-linking GTP-binding assay; proteolytic digestion experiments to determine membrane topology; biochemical fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted GTP binding, molecular cloning with domain analysis, proteolytic protection, multiple orthogonal methods in single study\",\n      \"pmids\": [\"7844142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The amino-terminal 140 residues of SR alpha constitute a membrane-binding domain that forms a protease-resistant folding unit and is the major site of tight binding with SR beta (SRPRB), indicating SR beta plays a role in the membrane assembly of SR alpha. SR alpha is not integrated into the ER membrane but is peripherally associated.\",\n      \"method\": \"Deletion mutagenesis of SR alpha, cell-free translation, microsome binding assays, alkaline carbonate extraction supplemented with 1 M NaSCN, proteolytic protection assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple biochemical assays in single study; mechanistic conclusion about SR beta binding domain confirmed\",\n      \"pmids\": [\"7797564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Assembly of SR alpha onto the ER membrane occurs via a two-step mechanism (targeting to ER, then anchoring on the cytoplasmic face) that is distinct from SRP-dependent targeting. Both anchoring and translocation activity could be reconstituted in vitro, demonstrating functional ER membrane assembly of SR alpha that restores translocation activity.\",\n      \"method\": \"Cell-free reconstitution assay for SR alpha membrane assembly; N-ethylmaleimide-inactivated ER microsomes used to assess anchoring and translocation activity independently\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with functional readout, single lab, two orthogonal assays (anchoring + translocation)\",\n      \"pmids\": [\"2537835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of SR beta (SRPRB)-GTP in complex with the interaction domain of SR alpha at 1.7 Å resolution revealed that the binding interface overlaps largely with the switch 1 region of SR beta. Biochemical data showed that eukaryotic SR is a conditional (not obligate) heterodimer, and that the GTP/GDP switch cycle of SR beta functions as a regulatory switch for receptor dimerization.\",\n      \"method\": \"X-ray crystallography at 1.7 Å; supporting biochemical binding assays to test conditional heterodimer formation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus biochemical validation of conditional dimerization; rigorous single study with orthogonal structural and biochemical methods\",\n      \"pmids\": [\"12654246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SR beta (SRPRB) is required for assembly of the N-glycosylation-competent translocon at the ER. Guanine analog chemical probes or mutation of the SR beta GTP-binding site caused an N-glycosylation-deficient phenotype without altering the SR alpha/SR beta association, but both approaches reduced the association of SR beta with the oligosaccharyltransferase (OST) complex, revealing a previously unrecognized function of SR beta in coordinating ER translation with N-glycosylation.\",\n      \"method\": \"High-throughput screening of guanine analog chemical probes; GTP-binding site mutagenesis; co-immunoprecipitation of SR beta with OST complex; N-glycosylation functional assays; CRISPR/Cas9 SRPRB knockout cell lines\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of active site + chemical probe + co-IP of OST complex + functional glycosylation assay + KO cell lines; multiple orthogonal methods in single study\",\n      \"pmids\": [\"36921042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of SRPRB caused profound destabilization of SRA (SR alpha), demonstrating that SR beta is required for SR alpha protein stability. SR double-knockout (SRPRB KO + siRNA SRPRA) cells were viable and showed that steady-state mRNA localization to the ER is largely SR-independent.\",\n      \"method\": \"CRISPR/Cas9 SRPRB knockout; siRNA silencing; cell fractionation; deep sequencing of ER-associated and cytosolic mRNAs; 4-thiouridine pulse-labeling/4SU-seq\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional and molecular readout (SR alpha destabilization), validated by orthogonal sequencing approach; single lab but multiple methods\",\n      \"pmids\": [\"37643813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ectopic expression of APMCF1 (SRPRB) in HHCC hepatocellular carcinoma cells (which lack endogenous APMCF1) inhibited cell growth and induced G1 cell cycle arrest associated with up-regulation of p21 and down-regulation of TIMP3, as assessed by cell cycle gene chip analysis. Conversely, RNAi-mediated knockdown of APMCF1 in HepG2 cells promoted cell growth.\",\n      \"method\": \"Liposome-mediated transfection for overexpression; RNAi knockdown; cell cycle gene chip analysis; growth assays\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression/knockdown with gene chip downstream readout but no direct mechanistic pathway validation; limited controls described in abstract\",\n      \"pmids\": [\"17080297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APMCF1 (SRPRB) protein is localized to the cytoplasm of COS-7 cells when expressed as an EGFP fusion protein.\",\n      \"method\": \"Transient transfection of pEGFP-APMCF1 fusion construct in COS-7 cells; fluorescence microscopy\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment by fluorescence microscopy, single lab, no functional consequence directly linked to localization in this study\",\n      \"pmids\": [\"19664239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cardiac-specific overexpression of Srprb in pressure-overload heart failure mice exacerbated ventricular remodeling, structural/electrical abnormalities, and ventricular arrhythmia incidence, while Srprb knockdown improved these parameters. Mechanistically, Srprb promoted arrhythmia vulnerability by activating endoplasmic reticulum stress and the TLR4/CaMKII/NF-κB signaling pathway. In vitro, Srprb modulation regulated angiotensin II-induced cardiomyocyte hypertrophy and TGF-β-induced fibroblast fibrosis.\",\n      \"method\": \"Adeno-associated virus-mediated cardiac-specific overexpression/knockdown in mice; aortic banding pressure-overload model; echocardiography; ECG; in vivo electrophysiology; adenovirus transfection of primary neonatal cardiomyocytes and fibroblasts; pathway inhibitor experiments; molecular and pathological analyses\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with functional cardiac phenotype, pathway inhibitor mechanistic confirmation, in vitro cellular validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41568549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of SRPRB in TNBC cell lines significantly inhibited proliferation, migration, and invasion, induced cell apoptosis, and suppressed the WNT signaling pathway as measured by expression of key WNT pathway regulatory proteins.\",\n      \"method\": \"siRNA/shRNA knockdown; CCK-8 and colony formation assays; Transwell and wound healing assays; flow cytometry; Hoechst staining; Western blot for WNT pathway proteins\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with multiple cellular readouts, WNT pathway association inferred from Western blot protein levels without direct epistasis or rescue experiments\",\n      \"pmids\": [\"41875940\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRPRB (SR beta) is an integral ER membrane GTPase that anchors SR alpha to the ER membrane, forms a conditional heterodimer with SR alpha regulated by its GTP/GDP switch cycle (as revealed by a 1.7 Å crystal structure), stimulates GTP binding and hydrolysis by SRP54 as part of a three-GTPase cascade driving cotranslational protein targeting to the ER, and additionally recruits the oligosaccharyltransferase complex to coordinate N-glycosylation of translocating proteins; loss of SRPRB destabilizes SR alpha and, beyond its canonical SRP receptor role, SRPRB overexpression activates ER stress and the TLR4/CaMKII/NF-κB pathway to promote cardiac hypertrophy, fibrosis, and arrhythmia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRPRB (SR beta) is the integral ER membrane GTPase subunit of the heterodimeric signal recognition particle (SRP) receptor, which mediates cotranslational targeting of secretory and membrane proteins to the ER [#0, #1]. SRPRB anchors the peripherally associated SR alpha subunit to the ER membrane through a tight interaction with the amino-terminal membrane-binding domain of SR alpha, and is required for SR alpha membrane assembly and protein stability [#2, #3, #7]. As a member of the GTPase superfamily, SRPRB binds GTP specifically, and together with SR alpha stimulates GTP binding and hydrolysis by SRP54 in a three-GTPase cascade that drives protein targeting [#1, #2]. A 1.7 \\u00c5 crystal structure of SRPRB-GTP bound to the SR alpha interaction domain showed that the binding interface overlaps the switch 1 region, establishing eukaryotic SR as a conditional heterodimer whose dimerization is governed by the SRPRB GTP/GDP switch cycle [#5]. Beyond targeting, the GTP-binding activity of SRPRB is required to recruit the oligosaccharyltransferase (OST) complex and assemble an N-glycosylation-competent translocon, coordinating ER translation with N-glycosylation [#6]. In the heart, cardiac-specific overexpression of Srprb exacerbates ventricular remodeling and arrhythmia by activating ER stress and TLR4/CaMKII/NF-\\u03baB signaling [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established that the SRP receptor is not a single protein but a tight, stoichiometric heterodimer, defining SR beta/SRPRB as an obligate partner of SR alpha at the ER membrane.\",\n      \"evidence\": \"SRP-Sepharose affinity chromatography, reciprocal immunoprecipitation, and sucrose gradient fractionation of liver microsomes\",\n      \"pmids\": [\"3021779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which subunit carries enzymatic/GTPase activity\", \"Membrane topology of each subunit unresolved\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identified SR beta as a GTP-binding protein and placed it within a three-GTPase cascade, answering how the receptor regulates SRP54 during targeting.\",\n      \"evidence\": \"In vitro GTP-binding and GTPase assays with purified SRP and SRP receptor components\",\n      \"pmids\": [\"8247130\", \"8299417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GTP-dependent regulation not resolved\", \"Order and kinetics of the GTPase switches not fully defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved the membrane architecture of the receptor by cloning SR beta as an integral transmembrane GTPase that anchors the peripheral SR alpha, defining the basis of receptor assembly.\",\n      \"evidence\": \"cDNA cloning and domain analysis, UV cross-linking GTP-binding assay, proteolytic protection topology, and biochemical fractionation; deletion mutagenesis localizing the SR alpha membrane-binding domain\",\n      \"pmids\": [\"7844142\", \"7797564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level interface between SR alpha and SR beta not yet defined\", \"Regulatory role of the GTP/GDP cycle in dimerization not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural mechanism for receptor dimerization, showing SR is a conditional heterodimer controlled by the SR beta nucleotide state.\",\n      \"evidence\": \"1.7 \\u00c5 X-ray crystal structure of SR beta-GTP bound to the SR alpha interaction domain with supporting biochemical binding assays\",\n      \"pmids\": [\"12654246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full assembled receptor with membrane context\", \"GDP-bound and apo states not structurally compared in same study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SRPRB function beyond targeting by showing its GTP-binding activity recruits the OST complex to build an N-glycosylation-competent translocon.\",\n      \"evidence\": \"Guanine analog chemical probes, GTP-binding site mutagenesis, co-IP of SR beta with OST complex, N-glycosylation assays, and CRISPR/Cas9 knockout cells\",\n      \"pmids\": [\"36921042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical contacts between SRPRB and specific OST subunits not mapped\", \"Whether OST recruitment is concurrent with or sequential to targeting unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined SRPRB as a determinant of SR alpha protein stability and tested the requirement of the receptor for ER mRNA localization.\",\n      \"evidence\": \"CRISPR/Cas9 SRPRB knockout plus siRNA double-knockout, cell fractionation, and 4SU-seq deep sequencing of ER-associated mRNAs\",\n      \"pmids\": [\"37643813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SR alpha destabilization upon SRPRB loss not defined\", \"Viability of double-knockout implies redundant targeting pathways not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked SRPRB dosage to cardiac pathology, showing overexpression drives arrhythmia and remodeling through ER stress and TLR4/CaMKII/NF-\\u03baB signaling.\",\n      \"evidence\": \"AAV cardiac-specific overexpression/knockdown in pressure-overload mice with echocardiography, ECG, in vivo electrophysiology, and pathway inhibitor experiments in primary cardiomyocytes and fibroblasts\",\n      \"pmids\": [\"41568549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a canonical SRP receptor subunit engages TLR4/CaMKII/NF-\\u03baB is mechanistically unexplained\", \"Whether the phenotype depends on SRPRB GTPase/targeting function not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Associated SRPRB with cancer cell proliferation and migration phenotypes in TNBC, implicating WNT signaling.\",\n      \"evidence\": \"siRNA/shRNA knockdown with proliferation, migration, invasion, apoptosis assays and Western blot of WNT pathway proteins\",\n      \"pmids\": [\"41875940\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"WNT pathway link inferred from protein levels without epistasis or rescue\", \"Single-lab knockdown without orthogonal validation or in vivo support\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unclear how the canonical ER-membrane SRP-receptor GTPase function of SRPRB mechanistically connects to its reported roles in cell proliferation, cardiac remodeling, and WNT/NF-\\u03baB signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experiments distinguish targeting-dependent from targeting-independent disease functions\", \"Cytoplasmic localization reports conflict with established integral ER membrane topology\", \"Direct effectors connecting SRPRB to NF-\\u03baB or WNT not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"SRP receptor (SR alpha/SR beta heterodimer)\"],\n    \"partners\": [\"SRPRA\", \"SRP54\", \"OST complex\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}