{"gene":"MRPS31","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2001,"finding":"MRPS31 (MRP-S31) was identified as one of 15 mitochondria-specific proteins unique to the mammalian mitochondrial ribosome small (28S) subunit, with no homologs in bacterial, chloroplast, archaebacterial, or cytosolic ribosomes, establishing it as a structural component of the mammalian mitoribosome small subunit.","method":"Proteolytic digestion of purified 28S mitoribosomal subunits followed by LC/MS/MS peptide sequencing and EST database searching","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution and mass spectrometry identification of subunit composition; foundational study","pmids":["11279123"],"is_preprint":false},{"year":2015,"finding":"Cryo-EM structure of the intact human mitoribosome at 3.5 Å resolution revealed MRPS31 (mS31) as one of 80 extensively interconnected proteins in the mitoribosome, with the small subunit head domain and mRNA channel being highly remodeled relative to bacterial ribosomes; the structure provides the molecular framework for MRPS31's position within the mitoribosomal small subunit.","method":"Single-particle cryo-electron microscopy at 3.5 Å resolution of the intact human mitoribosome","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with direct visualization of MRPS31 within the intact mitoribosome","pmids":["25838379"],"is_preprint":false},{"year":2021,"finding":"MRPS31 deficiency caused by somatic copy number loss disrupts whole mitoribosome assembly in hepatoma cell lines (JHH5, HepG2, Hep3B, SNU449). MRPS31 suppression enhanced hepatoma cell invasiveness through upregulation of MMP7 and COL1A1; COL1A1 modulated invasiveness via ZEB1-mediated epithelial-to-mesenchymal transition, mechanistically linking MRPS31 loss to mitochondrial deregulation and cancer aggressiveness.","method":"Endogenous SCNA-dependent MRPS31 expression analysis in hepatoma cell lines; functional studies of mitoribosome assembly, invasion assays, gene expression analysis for MMP7, COL1A1, ZEB1","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function with defined cellular phenotypes (assembly disruption, invasion) and pathway placement (ZEB1/EMT), single lab","pmids":["34772924"],"is_preprint":false},{"year":2021,"finding":"GST pulldown of recombinant MRPS31 from HEK293 cell lysate followed by nLC/MS/MS identified protein-protein interactions for MRPS31; network analysis revealed putative roles in tumourigenic cellular processes. Co-expression module analysis linked MRPS31 to acyl-CoA dehydrogenase interactions in fatty acid oxidation regulated by BDNF signalling, and MRPS31 was found overexpressed in breast cancer cell lines.","method":"GST fusion protein pulldown with HEK293 cell lysate followed by nLC/MS/MS; cancer cell line expression screening; co-expression module analysis","journal":"Journal of biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — single GST pulldown without reciprocal validation; interactome assignments are putative","pmids":["34492114"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the LRPPRC-SLIRP-mRNA-mitoribosome complex showed that LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 (MRPS31) through recognition of LRPPRC helical repeats, forming a corridor for mRNA handoff to the mitoribosome. This defines MRPS31's N-terminus as a docking site for the mRNA delivery factor LRPPRC during mitochondrial translation initiation.","method":"Cryo-electron microscopy structure of LRPPRC-SLIRP-mRNA-mitoribosome complex; RNA sequencing, metabolic labeling, and mitoribosome profiling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with direct visualization of MRPS31 N-terminus interaction with LRPPRC, supported by functional profiling data","pmids":["39134711"],"is_preprint":false},{"year":2024,"finding":"A missense mutation in C. elegans mrps-31 (encoding the mitoribosome small subunit protein S31) was identified as a unique activator of the mitochondrial unfolded protein response (UPRmt), confirming that MRPS-31 is required for normal mitoribosome function; loss of mrps-31 causes mitochondrial stress and impairs organismal development.","method":"Genetic screen in C. elegans; causality confirmed by allele characterization; UPRmt reporter assays; developmental phenotype analysis","journal":"microPublication biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined molecular phenotype (UPRmt activation) in an orthologous organism, single lab","pmids":["39410965"],"is_preprint":false}],"current_model":"MRPS31 is a mitochondria-specific structural component of the small (28S) subunit of the mammalian mitoribosome whose N-terminus serves as a docking site for the mRNA delivery factor LRPPRC, forming a corridor for mitochondrial mRNA handoff during translation; loss of MRPS31 disrupts mitoribosome assembly, activates the mitochondrial unfolded protein response, and in hepatocellular carcinoma promotes invasiveness via COL1A1/ZEB1-mediated epithelial-to-mesenchymal transition."},"narrative":{"teleology":[{"year":2001,"claim":"Identifying MRPS31 as a mammalian-specific mitoribosomal component established that the 28S small subunit contains a substantial cohort of proteins absent from bacterial ribosomes, raising the question of what specialized functions these additions confer.","evidence":"LC/MS/MS sequencing of purified 28S mitoribosomal subunit proteins combined with EST database matching","pmids":["11279123"],"confidence":"High","gaps":["No structural information on where MRPS31 sits within the small subunit","No functional consequence of MRPS31 loss tested","No interaction partners identified"]},{"year":2015,"claim":"Cryo-EM visualization of MRPS31 within the intact human mitoribosome at near-atomic resolution resolved its position in the remodeled small subunit head domain, providing the structural framework needed to understand its role in mRNA handling.","evidence":"Single-particle cryo-EM of the intact human mitoribosome at 3.5 Å resolution","pmids":["25838379"],"confidence":"High","gaps":["Specific molecular contacts between MRPS31 and mRNA or translation factors not yet defined","Functional consequences of MRPS31 perturbation still untested"]},{"year":2021,"claim":"Demonstrating that MRPS31 deficiency disrupts whole mitoribosome assembly and enhances hepatoma invasiveness via COL1A1/ZEB1-dependent EMT established that MRPS31 loss has both organellar and oncogenic consequences.","evidence":"SCNA-driven MRPS31 suppression in hepatoma cell lines; mitoribosome assembly assays, invasion assays, and gene expression analysis","pmids":["34772924"],"confidence":"Medium","gaps":["Whether the pro-invasive phenotype is a direct consequence of mitoribosome dysfunction or involves additional MRPS31 functions is unresolved","Findings from a single laboratory; not independently replicated","Mechanism connecting mitoribosome assembly failure to COL1A1/ZEB1 upregulation is unclear"]},{"year":2024,"claim":"Cryo-EM capture of the LRPPRC–SLIRP–mRNA complex docked onto the mitoribosome revealed that MRPS31's N-terminus directly contacts LRPPRC helical repeats, defining a mRNA handoff corridor and assigning MRPS31 a specific role in mitochondrial translation initiation.","evidence":"Cryo-EM of the LRPPRC-SLIRP-mRNA-mitoribosome complex; mitoribosome profiling and metabolic labeling","pmids":["39134711"],"confidence":"High","gaps":["Whether mRNA handoff through the MRPS31–LRPPRC interface is transcript-selective is unknown","No mutagenesis of the MRPS31 N-terminal docking residues to confirm functional necessity"]},{"year":2024,"claim":"A C. elegans genetic screen identified mrps-31 loss as a specific activator of the mitochondrial unfolded protein response, confirming cross-species conservation of its essential role in mitoribosome function and linking its loss to mitochondrial proteotoxic stress.","evidence":"Forward genetic screen in C. elegans with UPRmt reporter assays and developmental phenotype analysis","pmids":["39410965"],"confidence":"Medium","gaps":["Whether UPRmt activation reflects impaired mitoribosome assembly, stalled translation, or both is not distinguished","Mammalian UPRmt activation upon MRPS31 loss not yet demonstrated"]},{"year":null,"claim":"The mechanism by which MRPS31 loss triggers downstream transcriptional programs (e.g., EMT, UPRmt) and whether its N-terminal LRPPRC-docking function is required for mRNA selectivity during mitochondrial translation remain open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure-guided mutagenesis of MRPS31 N-terminal residues contacting LRPPRC","No reconstituted in vitro translation assay testing MRPS31's contribution to mRNA delivery","Signaling cascade from mitoribosome deficiency to EMT gene activation is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4]}],"complexes":["mitochondrial small ribosomal subunit (28S)"],"partners":["LRPPRC","SLIRP","MRPS39"],"other_free_text":[]},"mechanistic_narrative":"MRPS31 (mS31) is a mitochondria-specific structural protein of the small (28S) subunit of the mammalian mitoribosome, with no homologs in bacterial or cytosolic ribosomes [PMID:11279123]. High-resolution cryo-EM structures place MRPS31 within the extensively remodeled small subunit head domain, and its N-terminus serves as a docking site for the mRNA delivery factor LRPPRC, forming a corridor that channels mitochondrial mRNAs to the decoding center during translation initiation [PMID:25838379, PMID:39134711]. Loss of MRPS31 disrupts mitoribosome assembly, activates the mitochondrial unfolded protein response, and in hepatocellular carcinoma promotes invasiveness via COL1A1/ZEB1-mediated epithelial-to-mesenchymal transition [PMID:34772924, PMID:39410965]."},"prefetch_data":{"uniprot":{"accession":"Q92665","full_name":"Small ribosomal subunit protein mS31","aliases":["28S ribosomal protein S31, mitochondrial","MRP-S31","S31mt","Imogen 38"],"length_aa":395,"mass_kda":45.3,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q92665/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPS31","classification":"Common 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPS31"},"hgnc":{"alias_symbol":["IMOGN38","mS31"],"prev_symbol":[]},"alphafold":{"accession":"Q92665","domains":[{"cath_id":"-","chopping":"326-391","consensus_level":"high","plddt":91.9047,"start":326,"end":391},{"cath_id":"1.10.287","chopping":"154-194","consensus_level":"high","plddt":87.8012,"start":154,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92665","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92665-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92665-F1-predicted_aligned_error_v6.png","plddt_mean":66.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPS31","jax_strain_url":"https://www.jax.org/strain/search?query=MRPS31"},"sequence":{"accession":"Q92665","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92665.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92665/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92665"}},"corpus_meta":[{"pmid":"32987154","id":"PMC_32987154","title":"Expression 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The structure of the human mitochondrial ribosome.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25838379","citation_count":417,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34800366","id":"PMC_34800366","title":"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34800366","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27023846","id":"PMC_27023846","title":"Structure and Function of the Mitochondrial Ribosome.","date":"2016","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27023846","citation_count":217,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23973329","id":"PMC_23973329","title":"TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23973329","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27173435","id":"PMC_27173435","title":"An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27173435","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23473034","id":"PMC_23473034","title":"GRSF1 regulates RNA processing in mitochondrial RNA granules.","date":"2013","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23473034","citation_count":198,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32203420","id":"PMC_32203420","title":"Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32203420","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11279123","id":"PMC_11279123","title":"The small subunit of the mammalian mitochondrial ribosome. Identification of the full complement of ribosomal proteins present.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11279123","citation_count":189,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21958,"output_tokens":1030,"usd":0.040662},"stage2":{"model":"claude-opus-4-6","input_tokens":4229,"output_tokens":1532,"usd":0.089167},"total_usd":0.299826,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":33431,"output_tokens":2419,"usd":0.068289},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5156,"output_tokens":1681,"usd":0.101708}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"MRPS31 (mS31) is a mitoribosomal small subunit protein whose N-terminus directly interacts with LRPPRC through recognition of LRPPRC helical repeats; this interaction, together with mS39, forms a corridor for handoff of mRNA from LRPPRC-SLIRP to the mitoribosome, enabling transcript-specific regulation of mitochondrial translation.\",\n      \"method\": \"Cryo-electron microscopy structure of LRPPRC-SLIRP-mRNA-mitoribosome complex; RNA sequencing, metabolic labeling, and mitoribosome profiling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional validation by multiple orthogonal methods (ribosome profiling, metabolic labeling, RNA-seq)\",\n      \"pmids\": [\"39134711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MRPS31 deficiency disrupts whole mitoribosome assembly in hepatoma cells, leading to enhanced cell invasiveness through upregulation of MMP7 and COL1A1; COL1A1 modulates invasiveness via ZEB1-mediated epithelial-to-mesenchymal transition.\",\n      \"method\": \"Loss-of-function using hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, SNU449); mitoribosome assembly assay; invasion assays; gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"34772924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MRPS31 protein participates in protein-protein interactions with mitochondrial ribosomal small subunit components and other cellular proteins; GST pulldown from HEK293 cell lysate identified interaction partners linked to fatty acid oxidation and tumourigenic processes.\",\n      \"method\": \"GST pulldown followed by nLC/MS/MS analysis; PPI network analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/MS experiment, no reciprocal validation of MRPS31-specific interactions\",\n      \"pmids\": [\"34492114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense mutation in C. elegans mrps-31 (ortholog of MRPS31), a component of the mitoribosome small subunit, causes activation of the mitochondrial unfolded protein response (UPRmt) and impairs organismal development, establishing MRPS-31 as required for normal mitoribosome function and mitochondrial proteostasis.\",\n      \"method\": \"Forward genetic screen; causality confirmed by allele characterization; UPRmt reporter assay; developmental phenotype analysis in C. elegans\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in a metazoan ortholog with defined molecular phenotype (UPRmt activation) and developmental readout\",\n      \"pmids\": [\"39410965\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPS31 (mS31) is a structural component of the mitoribosomal small subunit whose N-terminus directly contacts the mRNA delivery factor LRPPRC, forming a corridor for mitochondrial mRNA handoff to enable transcript-specific translation; loss of MRPS31 disrupts mitoribosome assembly, activates the mitochondrial unfolded protein response, and in hepatocellular carcinoma cells promotes invasiveness through COL1A1/ZEB1-mediated EMT.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- Papers about MRPS31 (canonical mitochondrial ribosomal protein S31): KEEP → Papers [8], [15], [43] from retrieved; [30] from gene2pubmed (identifies MRPS31 as part of 28S small subunit); [18] (cryo-EM structure of human mitoribosome includes mS31); [4] (LRPPRC-SLIRP structure showing mS31 interaction); [22] (mitochondrial proteome); [23] (mitoribosome structure/function review); [1] from retrieved (Mrp gene expression); also [20] from gene2pubmed (GRSF1/mitochondrial RNA granules - mentions mitoribosomal context).\n\n- Papers about MS31 as a minisatellite/VNTR probe (D7S21): EXCLUDE (alias collision) → [2],[3],[6],[7],[9],[11],[13],[16],[17],[19],[21],[22 retrieved],[23 retrieved],[24],[25],[27],[28],[29],[30 retrieved],[32],[34],[36],[37],[39],[40],[42],[45],[46],[47],[50],[51],[52]\n\n- Papers about MS31 as SPIN1 inhibitor compound: EXCLUDE (alias collision) → [5],[48],[49]\n\n- Fusarium moniliforme strain MS31: EXCLUDE (symbol collision, microbial) → [38],[41]\n\n- MRPS31P5 lncRNA/chimeric RNA (alt-locus product): EXCLUDE → [20 retrieved],[29 retrieved]\n\n- Large interactome/proteome papers where MRPS31 appears incidentally: these are KEEP as they provide interaction/localization data for MRPS31 specifically → [2],[4],[5],[6],[7],[8],[9],[10],[11],[17],[19],[20],[21],[27] from gene2pubmed (where relevant)\n\n- [10] retrieved (thyroid carcinoma gene identification - expression only): EXCLUDE\n- [11] retrieved (statin resistance - bioinformatic/RNAi, no MRPS31 mechanistic follow-up): EXCLUDE\n- [14] retrieved (cow transcriptome): EXCLUDE\n- [26] retrieved (T2D ML analysis): EXCLUDE\n- [33] retrieved (panda methylation): EXCLUDE\n- [44] retrieved (CRISPR screen - MRPS31 identified as survival gene, no mechanism): borderline EXCLUDE (no mechanistic finding for MRPS31)\n\n**KEPT papers with mechanistic findings:**\n\nFrom retrieved: [8], [15], [43], [1] (expression pattern only - exclude from discoveries), [4]\nFrom gene2pubmed: [30] (PMID:11279123), [18] (PMID:25838379), [4] (PMID:39134711), [23] (PMID:27023846), [22] (PMID:34800366), [17] (PMID:29395067 - BioID proximity), [20] (PMID:34079125 - BioID localization)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MRPS31 (MRP-S31) was identified as one of 15 mitochondria-specific proteins unique to the mammalian mitochondrial ribosome small (28S) subunit, with no homologs in bacterial, chloroplast, archaebacterial, or cytosolic ribosomes, establishing it as a structural component of the mammalian mitoribosome small subunit.\",\n      \"method\": \"Proteolytic digestion of purified 28S mitoribosomal subunits followed by LC/MS/MS peptide sequencing and EST database searching\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution and mass spectrometry identification of subunit composition; foundational study\",\n      \"pmids\": [\"11279123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cryo-EM structure of the intact human mitoribosome at 3.5 Å resolution revealed MRPS31 (mS31) as one of 80 extensively interconnected proteins in the mitoribosome, with the small subunit head domain and mRNA channel being highly remodeled relative to bacterial ribosomes; the structure provides the molecular framework for MRPS31's position within the mitoribosomal small subunit.\",\n      \"method\": \"Single-particle cryo-electron microscopy at 3.5 Å resolution of the intact human mitoribosome\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with direct visualization of MRPS31 within the intact mitoribosome\",\n      \"pmids\": [\"25838379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MRPS31 deficiency caused by somatic copy number loss disrupts whole mitoribosome assembly in hepatoma cell lines (JHH5, HepG2, Hep3B, SNU449). MRPS31 suppression enhanced hepatoma cell invasiveness through upregulation of MMP7 and COL1A1; COL1A1 modulated invasiveness via ZEB1-mediated epithelial-to-mesenchymal transition, mechanistically linking MRPS31 loss to mitochondrial deregulation and cancer aggressiveness.\",\n      \"method\": \"Endogenous SCNA-dependent MRPS31 expression analysis in hepatoma cell lines; functional studies of mitoribosome assembly, invasion assays, gene expression analysis for MMP7, COL1A1, ZEB1\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined cellular phenotypes (assembly disruption, invasion) and pathway placement (ZEB1/EMT), single lab\",\n      \"pmids\": [\"34772924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GST pulldown of recombinant MRPS31 from HEK293 cell lysate followed by nLC/MS/MS identified protein-protein interactions for MRPS31; network analysis revealed putative roles in tumourigenic cellular processes. Co-expression module analysis linked MRPS31 to acyl-CoA dehydrogenase interactions in fatty acid oxidation regulated by BDNF signalling, and MRPS31 was found overexpressed in breast cancer cell lines.\",\n      \"method\": \"GST fusion protein pulldown with HEK293 cell lysate followed by nLC/MS/MS; cancer cell line expression screening; co-expression module analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single GST pulldown without reciprocal validation; interactome assignments are putative\",\n      \"pmids\": [\"34492114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the LRPPRC-SLIRP-mRNA-mitoribosome complex showed that LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 (MRPS31) through recognition of LRPPRC helical repeats, forming a corridor for mRNA handoff to the mitoribosome. This defines MRPS31's N-terminus as a docking site for the mRNA delivery factor LRPPRC during mitochondrial translation initiation.\",\n      \"method\": \"Cryo-electron microscopy structure of LRPPRC-SLIRP-mRNA-mitoribosome complex; RNA sequencing, metabolic labeling, and mitoribosome profiling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with direct visualization of MRPS31 N-terminus interaction with LRPPRC, supported by functional profiling data\",\n      \"pmids\": [\"39134711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense mutation in C. elegans mrps-31 (encoding the mitoribosome small subunit protein S31) was identified as a unique activator of the mitochondrial unfolded protein response (UPRmt), confirming that MRPS-31 is required for normal mitoribosome function; loss of mrps-31 causes mitochondrial stress and impairs organismal development.\",\n      \"method\": \"Genetic screen in C. elegans; causality confirmed by allele characterization; UPRmt reporter assays; developmental phenotype analysis\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined molecular phenotype (UPRmt activation) in an orthologous organism, single lab\",\n      \"pmids\": [\"39410965\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPS31 is a mitochondria-specific structural component of the small (28S) subunit of the mammalian mitoribosome whose N-terminus serves as a docking site for the mRNA delivery factor LRPPRC, forming a corridor for mitochondrial mRNA handoff during translation; loss of MRPS31 disrupts mitoribosome assembly, activates the mitochondrial unfolded protein response, and in hepatocellular carcinoma promotes invasiveness via COL1A1/ZEB1-mediated epithelial-to-mesenchymal transition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MRPS31 (mS31) is a structural subunit of the mitochondrial ribosomal small subunit required for mitoribosome assembly and mitochondrial translation. Its N-terminus directly contacts the mRNA delivery factor LRPPRC through recognition of LRPPRC helical repeats, forming—together with mS39—a corridor that hands off mRNA from the LRPPRC–SLIRP complex to the mitoribosome for transcript-specific translational regulation [PMID:39134711]. Loss of MRPS31 disrupts whole mitoribosome assembly and activates the mitochondrial unfolded protein response, impairing organismal development in C. elegans [PMID:34772924, PMID:39410965]. In hepatocellular carcinoma cells, MRPS31 deficiency promotes invasiveness through upregulation of COL1A1 and ZEB1-mediated epithelial-to-mesenchymal transition [PMID:34772924].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that MRPS31 is required for mitoribosome assembly and that its loss has consequences beyond translation—specifically enhancing hepatoma cell invasiveness through a COL1A1/ZEB1/EMT axis—linked a mitoribosomal structural protein to cancer cell behavior.\",\n      \"evidence\": \"Loss-of-function in hepatoma cell lines (JHH5, HepG2, Hep3B, SNU449) with mitoribosome assembly assays, invasion assays, and gene expression profiling\",\n      \"pmids\": [\"34772924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which mitoribosome assembly defect triggers COL1A1 upregulation is not defined\",\n        \"Results obtained in a single laboratory and limited to hepatoma cell lines\",\n        \"No in vivo tumor model validation\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A GST pulldown–mass spectrometry study identified MRPS31 interaction partners, tentatively connecting it to fatty acid oxidation and tumorigenic processes, but without reciprocal validation these interactions remain provisional.\",\n      \"evidence\": \"GST pulldown from HEK293 lysate followed by nLC/MS/MS and PPI network analysis\",\n      \"pmids\": [\"34492114\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single pulldown experiment without reciprocal or orthogonal validation of specific interactions\",\n        \"Endogenous relevance of identified partners not tested\",\n        \"No direct functional follow-up on fatty acid oxidation link\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM visualization of the LRPPRC–SLIRP–mRNA–mitoribosome complex revealed the precise molecular mechanism by which MRPS31 participates in mitochondrial mRNA delivery: its N-terminus directly engages LRPPRC helical repeats, co-forming a corridor with mS39 that channels mRNA to the decoding site for transcript-specific translation.\",\n      \"evidence\": \"Cryo-EM structure complemented by ribosome profiling, metabolic labeling, and RNA-seq\",\n      \"pmids\": [\"39134711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural snapshots do not reveal the kinetics or directionality of the mRNA handoff\",\n        \"Whether specific MRPS31 residues are individually required for the LRPPRC interaction has not been mutationally dissected\",\n        \"Regulatory inputs that modulate this corridor are unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A forward genetic screen in C. elegans demonstrated that a missense mutation in the MRPS31 ortholog (mrps-31) activates the mitochondrial unfolded protein response and impairs development, establishing an in vivo role in mitochondrial proteostasis across species.\",\n      \"evidence\": \"Forward genetic screen with allele characterization, UPRmt reporter assay, and developmental phenotyping in C. elegans\",\n      \"pmids\": [\"39410965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether UPRmt activation is a direct consequence of mitoribosome assembly failure or secondary to loss of specific OXPHOS subunits is unclear\",\n        \"Human disease relevance of MRPS31 loss-of-function mutations has not been demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the mRNA handoff corridor formed by MRPS31 and mS39 achieves transcript selectivity, whether MRPS31 mutations cause human mitochondrial disease, and what signaling pathways connect mitoribosome dysfunction to the EMT program observed in cancer cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical basis for transcript selectivity of the LRPPRC–mS31–mS39 corridor\",\n        \"No human Mendelian disease linked to MRPS31 mutations\",\n        \"Signaling intermediates between mitoribosome deficiency and COL1A1/ZEB1 EMT axis are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"mitoribosomal small subunit (28S)\"\n    ],\n    \"partners\": [\n      \"LRPPRC\",\n      \"SLIRP\",\n      \"MRPS39\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MRPS31 (mS31) is a mitochondria-specific structural protein of the small (28S) subunit of the mammalian mitoribosome, with no homologs in bacterial or cytosolic ribosomes [PMID:11279123]. High-resolution cryo-EM structures place MRPS31 within the extensively remodeled small subunit head domain, and its N-terminus serves as a docking site for the mRNA delivery factor LRPPRC, forming a corridor that channels mitochondrial mRNAs to the decoding center during translation initiation [PMID:25838379, PMID:39134711]. Loss of MRPS31 disrupts mitoribosome assembly, activates the mitochondrial unfolded protein response, and in hepatocellular carcinoma promotes invasiveness via COL1A1/ZEB1-mediated epithelial-to-mesenchymal transition [PMID:34772924, PMID:39410965].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying MRPS31 as a mammalian-specific mitoribosomal component established that the 28S small subunit contains a substantial cohort of proteins absent from bacterial ribosomes, raising the question of what specialized functions these additions confer.\",\n      \"evidence\": \"LC/MS/MS sequencing of purified 28S mitoribosomal subunit proteins combined with EST database matching\",\n      \"pmids\": [\"11279123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information on where MRPS31 sits within the small subunit\",\n        \"No functional consequence of MRPS31 loss tested\",\n        \"No interaction partners identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Cryo-EM visualization of MRPS31 within the intact human mitoribosome at near-atomic resolution resolved its position in the remodeled small subunit head domain, providing the structural framework needed to understand its role in mRNA handling.\",\n      \"evidence\": \"Single-particle cryo-EM of the intact human mitoribosome at 3.5 Å resolution\",\n      \"pmids\": [\"25838379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific molecular contacts between MRPS31 and mRNA or translation factors not yet defined\",\n        \"Functional consequences of MRPS31 perturbation still untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that MRPS31 deficiency disrupts whole mitoribosome assembly and enhances hepatoma invasiveness via COL1A1/ZEB1-dependent EMT established that MRPS31 loss has both organellar and oncogenic consequences.\",\n      \"evidence\": \"SCNA-driven MRPS31 suppression in hepatoma cell lines; mitoribosome assembly assays, invasion assays, and gene expression analysis\",\n      \"pmids\": [\"34772924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the pro-invasive phenotype is a direct consequence of mitoribosome dysfunction or involves additional MRPS31 functions is unresolved\",\n        \"Findings from a single laboratory; not independently replicated\",\n        \"Mechanism connecting mitoribosome assembly failure to COL1A1/ZEB1 upregulation is unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM capture of the LRPPRC–SLIRP–mRNA complex docked onto the mitoribosome revealed that MRPS31's N-terminus directly contacts LRPPRC helical repeats, defining a mRNA handoff corridor and assigning MRPS31 a specific role in mitochondrial translation initiation.\",\n      \"evidence\": \"Cryo-EM of the LRPPRC-SLIRP-mRNA-mitoribosome complex; mitoribosome profiling and metabolic labeling\",\n      \"pmids\": [\"39134711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mRNA handoff through the MRPS31–LRPPRC interface is transcript-selective is unknown\",\n        \"No mutagenesis of the MRPS31 N-terminal docking residues to confirm functional necessity\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A C. elegans genetic screen identified mrps-31 loss as a specific activator of the mitochondrial unfolded protein response, confirming cross-species conservation of its essential role in mitoribosome function and linking its loss to mitochondrial proteotoxic stress.\",\n      \"evidence\": \"Forward genetic screen in C. elegans with UPRmt reporter assays and developmental phenotype analysis\",\n      \"pmids\": [\"39410965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether UPRmt activation reflects impaired mitoribosome assembly, stalled translation, or both is not distinguished\",\n        \"Mammalian UPRmt activation upon MRPS31 loss not yet demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which MRPS31 loss triggers downstream transcriptional programs (e.g., EMT, UPRmt) and whether its N-terminal LRPPRC-docking function is required for mRNA selectivity during mitochondrial translation remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure-guided mutagenesis of MRPS31 N-terminal residues contacting LRPPRC\",\n        \"No reconstituted in vitro translation assay testing MRPS31's contribution to mRNA delivery\",\n        \"Signaling cascade from mitoribosome deficiency to EMT gene activation is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [\n      \"mitochondrial small ribosomal subunit (28S)\"\n    ],\n    \"partners\": [\n      \"LRPPRC\",\n      \"SLIRP\",\n      \"MRPS39\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}