{"gene":"SRI","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1988,"finding":"The human SRI gene (encoding sorcin, a ~22-kDa calcium-binding protein) was identified as co-amplified with MDR1 (ABCB1/P-glycoprotein) on chromosome 7 in multidrug-resistant human cancer cells, and its expression was found to be elevated alongside MDR1 amplification, establishing sorcin as a consistent co-amplified neighbor of P-glycoprotein in the human MDR genomic domain.","method":"Southern blotting, Northern blotting, gene amplification analysis in human MDR cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — direct gene amplification and expression analysis across multiple human MDR cell lines; foundational discovery paper with >160 citations","pmids":["2901906"],"is_preprint":false},{"year":1995,"finding":"Sorcin (SRI) associates with the cardiac ryanodine receptor (RyR2) at the sarcoplasmic reticulum; co-immunoprecipitation from cardiac myocytes demonstrated that sorcin co-precipitates with the ~565-kDa ryanodine receptor. Forced expression of sorcin in ryanodine receptor-negative fibroblasts induced accumulation of ryanodine receptor protein and reconstituted functional caffeine-sensitive calcium release channels, indicating sorcin stabilizes RyR2 and modulates calcium release channel activity.","method":"Co-immunoprecipitation from cardiac myocytes, immunoelectron microscopy localizing sorcin to sarcoplasmic reticulum, forced expression in heterologous cells with functional calcium imaging (caffeine-induced Ca²⁺ transients)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal co-IP, subcellular localization by immunoelectron microscopy, and functional reconstitution in heterologous cells; single rigorous paper with multiple orthogonal methods","pmids":["7592856"],"is_preprint":false},{"year":2010,"finding":"Sorcin (SRI) physically interacts with the mitochondrial chaperone TRAP1 (Hsp75) and localizes to mitochondria as a distinct isoform (<20 kDa); this interaction is required for sorcin's mitochondrial localization and TRAP1 stability. Depletion of TRAP1 reduces mitochondrial sorcin levels, while depletion of sorcin accelerates TRAP1 degradation. The sorcin–TRAP1 interaction contributes to protection against apoptosis induced by anti-cancer agents, and both proteins are co-upregulated in human colorectal carcinoma, linking sorcin to mitochondrial cytoprotection and multidrug resistance via the TRAP1 pathway.","method":"Proteomic analysis of TRAP1 co-immunoprecipitation complexes (mass spectrometry), fluorescence microscopy, Western blot of purified mitochondrial subfractions, shRNA/siRNA knockdown with functional apoptosis assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — co-IP proteomics, subcellular fractionation, reciprocal knockdown experiments with functional phenotypic readout; multiple orthogonal methods in a single study","pmids":["20647321"],"is_preprint":false}],"current_model":"Sorcin (SRI) is a 22-kDa calcium-binding protein that is co-amplified with MDR1/P-glycoprotein on chromosome 7 in multidrug-resistant cells; it localizes to the sarcoplasmic reticulum in cardiac muscle where it physically associates with and stabilizes the ryanodine receptor (RyR2) to modulate calcium release channel activity, and a distinct mitochondrial isoform interacts with the chaperone TRAP1 to promote cytoprotection and contribute to multidrug resistance."},"narrative":{"teleology":[{"year":1988,"claim":"The genomic basis of sorcin's association with multidrug resistance was established by demonstrating that SRI is co-amplified with MDR1 on chromosome 7 in human MDR cell lines, raising the question of whether sorcin has a functional role in drug resistance or is merely a bystander of gene amplification.","evidence":"Southern and Northern blotting across multiple human MDR cell lines","pmids":["2901906"],"confidence":"High","gaps":["No evidence for a direct functional contribution of sorcin to drug efflux or resistance","Mechanism of sorcin's normal cellular function was unknown","Whether sorcin overexpression alone is sufficient to confer resistance was untested"]},{"year":1995,"claim":"Sorcin's normal physiological function was revealed as a modulator of intracellular calcium release through direct physical association with the ryanodine receptor RyR2 at the sarcoplasmic reticulum, where it stabilizes RyR2 and enables caffeine-sensitive Ca²⁺ channel activity.","evidence":"Co-immunoprecipitation from cardiac myocytes, immunoelectron microscopy at the sarcoplasmic reticulum, and functional reconstitution of Ca²⁺ release in RyR2-negative fibroblasts","pmids":["7592856"],"confidence":"High","gaps":["Structural basis of the sorcin–RyR2 interaction is undefined","Whether calcium binding to sorcin's EF-hands is required for RyR2 modulation was not tested","Relevance of sorcin–RyR2 interaction to MDR phenotype was not addressed"]},{"year":2010,"claim":"A mechanistic link between sorcin and mitochondrial anti-apoptotic signaling was established by identifying a mitochondrial sorcin isoform that interacts with the chaperone TRAP1; reciprocal knockdown showed mutual stabilization, and the complex protects cells from chemotherapy-induced apoptosis.","evidence":"TRAP1 co-IP proteomics (mass spectrometry), mitochondrial subfractionation, shRNA/siRNA knockdown with apoptosis assays in colorectal carcinoma cells","pmids":["20647321"],"confidence":"High","gaps":["Direct binding interface between sorcin and TRAP1 is uncharacterized","Whether the mitochondrial isoform arises from alternative translation or processing is unknown","Relative contributions of RyR2 modulation versus TRAP1-mediated cytoprotection to drug resistance are unresolved"]},{"year":null,"claim":"It remains unknown how sorcin's calcium-sensing EF-hand domains differentially regulate its interactions with RyR2 and TRAP1, and whether sorcin's MDR contribution is mechanistically distinct from MDR1/P-glycoprotein-mediated drug efflux.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of sorcin in complex with RyR2 or TRAP1","No genetic loss-of-function models (knockout animal or patient mutations) for sorcin","Calcium-dependence of the sorcin–TRAP1 interaction has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["RYR2","TRAP1"],"other_free_text":[]},"mechanistic_narrative":"Sorcin (SRI) is a 22-kDa calcium-binding protein that functions in calcium signaling regulation, mitochondrial cytoprotection, and multidrug resistance. The SRI gene is genomically co-amplified with MDR1 (ABCB1) on chromosome 7 in multidrug-resistant human cancer cells, establishing its consistent overexpression in the MDR genomic domain [PMID:2901906]. Sorcin physically associates with the cardiac ryanodine receptor (RyR2) at the sarcoplasmic reticulum, where it stabilizes RyR2 protein levels and reconstitutes functional caffeine-sensitive calcium release channels [PMID:7592856]. A distinct mitochondrial isoform of sorcin interacts with the chaperone TRAP1, and reciprocal depletion experiments demonstrate mutual stabilization of sorcin and TRAP1, coupling sorcin to mitochondrial anti-apoptotic signaling and chemoresistance [PMID:20647321]."},"prefetch_data":{"uniprot":{"accession":"P30626","full_name":"Sorcin","aliases":["22 kDa protein","CP-22","CP22","V19"],"length_aa":198,"mass_kda":21.7,"function":"Calcium-binding protein that modulates excitation-contraction coupling in the heart. Contributes to calcium homeostasis in the heart sarcoplasmic reticulum. Modulates the activity of RYR2 calcium channels","subcellular_location":"Cytoplasm; Sarcoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P30626/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRI","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000075142","cell_line_id":"CID001916","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"NOL10","stoichiometry":10.0},{"gene":"ANAPC2","stoichiometry":0.2},{"gene":"ANLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001916","total_profiled":1310},"omim":[{"mim_id":"621558","title":"RETINAL DYSTROPHY, ZEITZ-HAN TYPE; RDZH","url":"https://www.omim.org/entry/621558"},{"mim_id":"621543","title":"UBIQUITIN-ASSOCIATED PROTEIN 1-LIKE PROTEIN; UBAP1L","url":"https://www.omim.org/entry/621543"},{"mim_id":"621307","title":"ALSAHAN-HARRIS SYNDROME; ALHAS","url":"https://www.omim.org/entry/621307"},{"mim_id":"620265","title":"CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE; CMYO2B","url":"https://www.omim.org/entry/620265"},{"mim_id":"619967","title":"CONGENITAL MYOPATHY 11; CMYO11","url":"https://www.omim.org/entry/619967"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":529.7}],"url":"https://www.proteinatlas.org/search/SRI"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P30626","domains":[{"cath_id":"1.10.238.10","chopping":"33-196","consensus_level":"medium","plddt":92.3113,"start":33,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30626","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30626-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30626-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRI","jax_strain_url":"https://www.jax.org/strain/search?query=SRI"},"sequence":{"accession":"P30626","fasta_url":"https://rest.uniprot.org/uniprotkb/P30626.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30626/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30626"}},"corpus_meta":[{"pmid":"17552105","id":"PMC_17552105","title":"Leishmania donovani and cutaneous leishmaniasis, Sri Lanka.","date":"2007","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17552105","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12752111","id":"PMC_12752111","title":"The molecular basis for the thalassaemias in Sri Lanka.","date":"2003","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/12752111","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24130516","id":"PMC_24130516","title":"Prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and serotonin transporter promoter genotype (SLC6A4) influence executive functions at 6 years of age.","date":"2013","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24130516","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8180591","id":"PMC_8180591","title":"Low prevalence of expression of p53 oncoprotein in oral carcinomas from Sri Lanka associated with betel and tobacco chewing.","date":"1993","source":"European journal of cancer. 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All other papers are about Sri Lanka (the country) or unrelated topics.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The SRI domain of Set2 directly associates with phosphorylated RNA Pol II to recruit Set2 to transcribed chromatin, and also recognizes linker DNA of chromatin, thereby controlling Set2 substrate specificity. Additionally, an auto-inhibitory domain (AID) of Set2 restricts Set2 activity to transcribed chromatin and fine-tunes SRI functions; AID mutations cause hyperactive Set2 in vivo and display a synthetic interaction with the histone chaperone FACT.\",\n      \"method\": \"Pol II-Set2 fusion constructs, in vivo chromatin assays, genetic epistasis with FACT, AID mutagenesis, and functional readouts of H3K36 methylation\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic and functional assays with multiple orthogonal approaches in a single study; single lab\",\n      \"pmids\": [\"25925577\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"The SRI domain of Set2 mediates recruitment to transcribed chromatin by directly binding phosphorylated RNA Pol II and also contacts linker DNA to control substrate specificity, while an adjacent auto-inhibitory domain (AID) restricts Set2 H3K36 methyltransferase activity to transcribed regions and modulates SRI function, together ensuring precise temporal control of H3K36 methylation during transcription elongation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about the canonical human protein SRI (Sorcin), a calcium-binding protein encoded by the SRI gene.\n\n**Classification:**\n\nFrom the retrieved 100 papers: The vast majority are about Sri Lanka (the country) or \"SRI\" as an abbreviation for serotonin reuptake inhibitor — all EXCLUDE (alias/geographic collision).\n\nPaper [18] (PMID:25925577) — about \"SRI domain\" of Set2 histone methyltransferase — EXCLUDE: SRI here is a domain within Set2, not the canonical SRI gene (Sorcin).\n\nPaper [32] (PMID:32185127) — about \"SRI-38832\" (a GLI1 inhibitor drug compound) — EXCLUDE: SRI here is a drug name, not the gene.\n\nFrom the gene2pubmed-curated papers:\n- PMID:2901906 — describes sorcin (the calcium-binding protein co-amplified with MDR genes, human homolog of hamster sorcin gene) — **KEEP**\n- PMID:7592856 — describes sorcin association with cardiac ryanodine receptor — **KEEP**\n- PMID:20647321 — describes sorcin interaction with TRAP1 in mitochondria — **KEEP**\n- PMID:16189514, 16169070, 25416956, 32296183, 26344197, etc. — large-scale interactome screens; SRI appears incidentally — include only if specific mechanistic findings about sorcin are described. These are large-scale screens without specific sorcin mechanistic findings — EXCLUDE for specific discoveries.\n- PMID:17215369 — about ST13/Parkinson's, not sorcin — EXCLUDE.\n- PMID:17643375 — transcription machinery; no specific sorcin finding — EXCLUDE.\n- PMID:15326289, 19056867, etc. — exosome proteomics; sorcin detected incidentally — EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"The human SRI gene (encoding sorcin, a ~22-kDa calcium-binding protein) was identified as co-amplified with MDR1 (ABCB1/P-glycoprotein) on chromosome 7 in multidrug-resistant human cancer cells, and its expression was found to be elevated alongside MDR1 amplification, establishing sorcin as a consistent co-amplified neighbor of P-glycoprotein in the human MDR genomic domain.\",\n      \"method\": \"Southern blotting, Northern blotting, gene amplification analysis in human MDR cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct gene amplification and expression analysis across multiple human MDR cell lines; foundational discovery paper with >160 citations\",\n      \"pmids\": [\"2901906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Sorcin (SRI) associates with the cardiac ryanodine receptor (RyR2) at the sarcoplasmic reticulum; co-immunoprecipitation from cardiac myocytes demonstrated that sorcin co-precipitates with the ~565-kDa ryanodine receptor. Forced expression of sorcin in ryanodine receptor-negative fibroblasts induced accumulation of ryanodine receptor protein and reconstituted functional caffeine-sensitive calcium release channels, indicating sorcin stabilizes RyR2 and modulates calcium release channel activity.\",\n      \"method\": \"Co-immunoprecipitation from cardiac myocytes, immunoelectron microscopy localizing sorcin to sarcoplasmic reticulum, forced expression in heterologous cells with functional calcium imaging (caffeine-induced Ca²⁺ transients)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal co-IP, subcellular localization by immunoelectron microscopy, and functional reconstitution in heterologous cells; single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"7592856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sorcin (SRI) physically interacts with the mitochondrial chaperone TRAP1 (Hsp75) and localizes to mitochondria as a distinct isoform (<20 kDa); this interaction is required for sorcin's mitochondrial localization and TRAP1 stability. Depletion of TRAP1 reduces mitochondrial sorcin levels, while depletion of sorcin accelerates TRAP1 degradation. The sorcin–TRAP1 interaction contributes to protection against apoptosis induced by anti-cancer agents, and both proteins are co-upregulated in human colorectal carcinoma, linking sorcin to mitochondrial cytoprotection and multidrug resistance via the TRAP1 pathway.\",\n      \"method\": \"Proteomic analysis of TRAP1 co-immunoprecipitation complexes (mass spectrometry), fluorescence microscopy, Western blot of purified mitochondrial subfractions, shRNA/siRNA knockdown with functional apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — co-IP proteomics, subcellular fractionation, reciprocal knockdown experiments with functional phenotypic readout; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"20647321\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Sorcin (SRI) is a 22-kDa calcium-binding protein that is co-amplified with MDR1/P-glycoprotein on chromosome 7 in multidrug-resistant cells; it localizes to the sarcoplasmic reticulum in cardiac muscle where it physically associates with and stabilizes the ryanodine receptor (RyR2) to modulate calcium release channel activity, and a distinct mitochondrial isoform interacts with the chaperone TRAP1 to promote cytoprotection and contribute to multidrug resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"The SRI domain of Set2 directly binds phosphorylated RNA Pol II to recruit Set2 to transcribed chromatin and also contacts linker DNA, thereby controlling Set2 substrate specificity for H3K36 methylation [PMID:25925577]. An adjacent auto-inhibitory domain (AID) restricts Set2 methyltransferase activity to transcribed regions and modulates SRI function; AID mutations produce hyperactive Set2 in vivo and display synthetic genetic interactions with the histone chaperone FACT [PMID:25925577].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving how Set2 is targeted to active genes and prevented from acting elsewhere, this study established that the SRI domain serves a dual role — binding phosphorylated Pol II for recruitment and contacting linker DNA for substrate selectivity — while the AID restricts ectopic H3K36 methylation.\",\n      \"evidence\": \"Pol II–Set2 fusion constructs, in vivo chromatin assays, AID mutagenesis, and genetic epistasis with FACT in S. cerevisiae\",\n      \"pmids\": [\"25925577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication of the dual SRI function (Pol II binding and linker-DNA recognition) has not been reported\",\n        \"Structural basis for AID-mediated autoinhibition is unresolved\",\n        \"Mechanism by which AID mutations synergize with FACT is not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural details of how the AID physically restrains catalytic activity and how SRI simultaneously engages Pol II and linker DNA remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the SRI–Pol II–nucleosome ternary complex\",\n        \"Quantitative contribution of linker-DNA binding versus Pol II interaction to chromatin targeting not separated\",\n        \"Whether AID regulation is conserved in mammalian SETD2 is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNA Pol II\", \"FACT\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to correct the pathway entries — they should use Reactome IDs, not GO terms. Let me fix that.\n\n```json\n{\n  \"mechanistic_narrative\": \"The SRI domain of Set2 directly binds phosphorylated RNA Pol II to recruit Set2 to transcribed chromatin and also contacts linker DNA, thereby controlling Set2 substrate specificity for H3K36 methylation [PMID:25925577]. An adjacent auto-inhibitory domain (AID) restricts Set2 methyltransferase activity to transcribed regions and modulates SRI function; AID mutations produce hyperactive Set2 in vivo and display synthetic genetic interactions with the histone chaperone FACT [PMID:25925577].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving how Set2 is targeted to active genes and prevented from acting elsewhere, this study established that the SRI domain serves a dual role — binding phosphorylated Pol II for recruitment and contacting linker DNA for substrate selectivity — while the AID restricts ectopic H3K36 methylation.\",\n      \"evidence\": \"Pol II–Set2 fusion constructs, in vivo chromatin assays, AID mutagenesis, and genetic epistasis with FACT in S. cerevisiae\",\n      \"pmids\": [\"25925577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication of the dual SRI function (Pol II binding and linker-DNA recognition) has not been reported\",\n        \"Structural basis for AID-mediated autoinhibition is unresolved\",\n        \"Mechanism by which AID mutations synergize with FACT is not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural details of how the AID physically restrains catalytic activity and how SRI simultaneously engages Pol II and linker DNA remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the SRI–Pol II–nucleosome ternary complex\",\n        \"Quantitative contribution of linker-DNA binding versus Pol II interaction to chromatin targeting not separated\",\n        \"Whether AID regulation is conserved in mammalian SETD2 is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RNA Pol II\", \"FACT\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Sorcin (SRI) is a 22-kDa calcium-binding protein that functions in calcium signaling regulation, mitochondrial cytoprotection, and multidrug resistance. The SRI gene is genomically co-amplified with MDR1 (ABCB1) on chromosome 7 in multidrug-resistant human cancer cells, establishing its consistent overexpression in the MDR genomic domain [PMID:2901906]. Sorcin physically associates with the cardiac ryanodine receptor (RyR2) at the sarcoplasmic reticulum, where it stabilizes RyR2 protein levels and reconstitutes functional caffeine-sensitive calcium release channels [PMID:7592856]. A distinct mitochondrial isoform of sorcin interacts with the chaperone TRAP1, and reciprocal depletion experiments demonstrate mutual stabilization of sorcin and TRAP1, coupling sorcin to mitochondrial anti-apoptotic signaling and chemoresistance [PMID:20647321].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"The genomic basis of sorcin's association with multidrug resistance was established by demonstrating that SRI is co-amplified with MDR1 on chromosome 7 in human MDR cell lines, raising the question of whether sorcin has a functional role in drug resistance or is merely a bystander of gene amplification.\",\n      \"evidence\": \"Southern and Northern blotting across multiple human MDR cell lines\",\n      \"pmids\": [\"2901906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No evidence for a direct functional contribution of sorcin to drug efflux or resistance\",\n        \"Mechanism of sorcin's normal cellular function was unknown\",\n        \"Whether sorcin overexpression alone is sufficient to confer resistance was untested\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Sorcin's normal physiological function was revealed as a modulator of intracellular calcium release through direct physical association with the ryanodine receptor RyR2 at the sarcoplasmic reticulum, where it stabilizes RyR2 and enables caffeine-sensitive Ca²⁺ channel activity.\",\n      \"evidence\": \"Co-immunoprecipitation from cardiac myocytes, immunoelectron microscopy at the sarcoplasmic reticulum, and functional reconstitution of Ca²⁺ release in RyR2-negative fibroblasts\",\n      \"pmids\": [\"7592856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the sorcin–RyR2 interaction is undefined\",\n        \"Whether calcium binding to sorcin's EF-hands is required for RyR2 modulation was not tested\",\n        \"Relevance of sorcin–RyR2 interaction to MDR phenotype was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A mechanistic link between sorcin and mitochondrial anti-apoptotic signaling was established by identifying a mitochondrial sorcin isoform that interacts with the chaperone TRAP1; reciprocal knockdown showed mutual stabilization, and the complex protects cells from chemotherapy-induced apoptosis.\",\n      \"evidence\": \"TRAP1 co-IP proteomics (mass spectrometry), mitochondrial subfractionation, shRNA/siRNA knockdown with apoptosis assays in colorectal carcinoma cells\",\n      \"pmids\": [\"20647321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between sorcin and TRAP1 is uncharacterized\",\n        \"Whether the mitochondrial isoform arises from alternative translation or processing is unknown\",\n        \"Relative contributions of RyR2 modulation versus TRAP1-mediated cytoprotection to drug resistance are unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how sorcin's calcium-sensing EF-hand domains differentially regulate its interactions with RyR2 and TRAP1, and whether sorcin's MDR contribution is mechanistically distinct from MDR1/P-glycoprotein-mediated drug efflux.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of sorcin in complex with RyR2 or TRAP1\",\n        \"No genetic loss-of-function models (knockout animal or patient mutations) for sorcin\",\n        \"Calcium-dependence of the sorcin–TRAP1 interaction has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RYR2\",\n      \"TRAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}