{"gene":"MRPL28","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2001,"finding":"MRPL28 was identified as a protein component of the human mitochondrial large ribosomal subunit (39S subunit), established as a homolog of bacterial ribosomal protein L28 and confirmed by mass spectrometry peptide sequencing of purified 39S subunits.","method":"Proteolytic digestion of purified 39S subunits followed by LC-MS/MS peptide sequencing and database searching","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical identification from purified mitoribosome; foundational proteomics study establishing 39S composition","pmids":["11551941"],"is_preprint":false},{"year":2009,"finding":"Knockdown of MRPL28 in pancreatic tumor cells decreased mitochondrial activity (oxidative phosphorylation) and increased compensatory glycolysis, but paradoxically decreased cellular growth in vitro while accelerating tumor growth in vivo, demonstrating that MRPL28 loss modulates the Warburg effect by reducing mitochondrial oxygen consumption and thereby relieving a rate-limiting constraint on tumor proliferation.","method":"shRNA knockdown of MRPL28 in pancreatic cancer cells; measurement of oxygen consumption, glycolysis, in vitro growth assays, and in vivo xenograft tumor growth assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with specific phenotypic readouts (O2 consumption, glycolysis, in vitro vs in vivo growth); single lab, multiple orthogonal readouts","pmids":["19753307"],"is_preprint":false},{"year":2014,"finding":"Cryo-EM structure of the human mitochondrial large ribosomal subunit at 3.4 Å resolution revealed MRPL28 as one of 48 proteins in the 39S subunit, establishing its structural position within the mitoribosome and showing extensive remodeling relative to bacterial ribosomes, with the large subunit specialized for translating hydrophobic membrane proteins.","method":"Single-particle cryo-electron microscopy at 3.4 Å resolution","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with near-atomic resolution defining subunit composition and architecture","pmids":["25278503"],"is_preprint":false}],"current_model":"MRPL28 is a structural protein component of the 39S large subunit of the human mitochondrial ribosome (confirmed by proteomics and cryo-EM), where it contributes to mitochondrial translation of membrane proteins; its loss reduces mitochondrial oxidative phosphorylation and increases glycolysis, and in tumor cells this reduction in oxygen consumption paradoxically accelerates in vivo tumor growth by relieving oxygen as a rate-limiting substrate."},"narrative":{"teleology":[{"year":2001,"claim":"The identity of MRPL28 as a bona fide subunit of the human 39S mitoribosomal large subunit was established, resolving the composition of the mammalian mitoribosome and assigning MRPL28 as the homolog of bacterial L28.","evidence":"LC-MS/MS peptide sequencing of purified human 39S subunits","pmids":["11551941"],"confidence":"High","gaps":["No structural context for where MRPL28 sits within the 39S subunit","Functional contribution of MRPL28 to translation not tested"]},{"year":2009,"claim":"MRPL28 loss was shown to impair mitochondrial oxidative phosphorylation and increase glycolysis, linking mitoribosomal function to metabolic reprogramming and demonstrating that reduced oxygen consumption can paradoxically promote tumor growth in vivo.","evidence":"shRNA knockdown in pancreatic cancer cells with oxygen consumption, glycolysis, and xenograft growth measurements","pmids":["19753307"],"confidence":"Medium","gaps":["Single cell line and lab; not independently replicated","Whether MRPL28 knockdown specifically impairs translation of particular mitochondrial mRNAs was not assessed","Mechanism by which reduced oxygen consumption accelerates in vivo growth (e.g., angiogenesis independence vs. diffusion advantage) was not resolved"]},{"year":2014,"claim":"Near-atomic cryo-EM resolved MRPL28's structural position within the 39S subunit, confirming it as an integral part of the extensively remodeled mammalian mitoribosome specialized for membrane protein translation.","evidence":"Single-particle cryo-EM of the human 39S subunit at 3.4 Å resolution","pmids":["25278503"],"confidence":"High","gaps":["Specific protein–protein or protein–rRNA contacts mediated by MRPL28 not individually characterized","Whether MRPL28 is required for ribosome assembly vs. translation catalysis is unknown"]},{"year":null,"claim":"It remains unknown whether MRPL28 plays a dedicated role in mitoribosome assembly, translational fidelity, or substrate selectivity beyond serving as a structural subunit, and whether its loss phenocopies other 39S subunit deficiencies in human disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No patient mutations or Mendelian disease link reported","No reconstitution or mutagenesis studies dissecting MRPL28-specific contacts","Role in mitoribosome assembly pathway not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1]}],"complexes":["39S mitoribosomal large subunit"],"partners":[],"other_free_text":[]},"mechanistic_narrative":"MRPL28 is a structural component of the 39S large subunit of the human mitochondrial ribosome, identified by mass spectrometry of purified subunits and positioned within the complex by cryo-EM at 3.4 Å resolution as one of 48 proteins in the remodeled mammalian mitoribosome [PMID:11551941, PMID:25278503]. As part of the mitoribosome, MRPL28 contributes to mitochondrial translation of hydrophobic membrane proteins essential for oxidative phosphorylation; its knockdown in pancreatic cancer cells reduces oxygen consumption and shifts metabolism toward glycolysis, paradoxically accelerating xenograft tumor growth by relieving oxygen as a rate-limiting substrate for proliferation [PMID:19753307]."},"prefetch_data":{"uniprot":{"accession":"Q13084","full_name":"Large ribosomal subunit protein bL28m","aliases":["39S ribosomal protein L28, mitochondrial","L28mt","MRP-L28","Melanoma antigen p15","Melanoma-associated antigen recognized by T-lymphocytes"],"length_aa":256,"mass_kda":30.2,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q13084/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPL28","classification":"Common Essential","n_dependent_lines":675,"n_total_lines":1208,"dependency_fraction":0.5587748344370861},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MRPL28","total_profiled":1310},"omim":[{"mim_id":"620646","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 59; COXPD59","url":"https://www.omim.org/entry/620646"},{"mim_id":"611845","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L39; MRPL39","url":"https://www.omim.org/entry/611845"},{"mim_id":"611838","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L30; MRPL30","url":"https://www.omim.org/entry/611838"},{"mim_id":"604853","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L28; MRPL28","url":"https://www.omim.org/entry/604853"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPL28"},"hgnc":{"alias_symbol":["p15","bL28m"],"prev_symbol":["MAAT1"]},"alphafold":{"accession":"Q13084","domains":[{"cath_id":"-","chopping":"37-42_51-209","consensus_level":"medium","plddt":94.8608,"start":37,"end":209}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13084","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13084-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13084-F1-predicted_aligned_error_v6.png","plddt_mean":92.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPL28","jax_strain_url":"https://www.jax.org/strain/search?query=MRPL28"},"sequence":{"accession":"Q13084","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13084.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13084/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13084"}},"corpus_meta":[{"pmid":"18185590","id":"PMC_18185590","title":"Epigenetic silencing 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Analysis of the complement of ribosomal proteins present.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11551941","citation_count":216,"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":"30833792","id":"PMC_30833792","title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833792","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20186120","id":"PMC_20186120","title":"A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20186120","citation_count":153,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19753307","id":"PMC_19753307","title":"Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19753307","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50840,"output_tokens":297,"usd":0.078488},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.256659,"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":61971,"output_tokens":1327,"usd":0.102909},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4235,"output_tokens":1160,"usd":0.075262}},"stage1_raw":"Looking at the corpus, I need to identify what gene \"MRPL28\" actually corresponds to. The retrieved papers are overwhelmingly about CDKN2B (p15/INK4b), a cyclin-dependent kinase inhibitor, and some papers about the mRNA export factor p15/NXT1 (TAP-p15 heterodimer). There is no mention of MRPL28 (mitochondrial ribosomal protein L28) in any of these abstracts. The gene symbol \"p15\" appears to collide across multiple unrelated proteins.\n\nSince none of the abstracts mention MRPL28 specifically, and all papers describe either CDKN2B (p15/INK4b) or NXT1 (p15 mRNA export factor) — neither of which is MRPL28 — I cannot extract any mechanistic discoveries about MRPL28 from this corpus.\n\n```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings about MRPL28 (mitochondrial ribosomal protein L28) are present in the available literature; all retrieved papers describe unrelated proteins sharing the 'p15' designation (CDKN2B/INK4b or NXT1/mRNA export factor).\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers actually about MRPL28 (mitochondrial ribosomal protein L28) versus the many papers about p15/CDKN2B (a CDK inhibitor), p15 PAF (PCNA-associated factor), p15 NXT1 (mRNA export), viral p15 proteins, and other unrelated genes.\n\nFrom the retrieved papers (1-100): Nearly all are about CDKN2B/p15(INK4b), p15PAF, NXT1/p15 (mRNA export factor), viral p15 proteins, or other unrelated p15 proteins. None appear to be about MRPL28 specifically.\n\nFrom the gene2pubmed papers (1-30): Several are relevant to MRPL28:\n- PMID:29 (Chen et al., 2009, PLoS One) — directly describes MRPL28 knockdown affecting mitochondrial activity and tumor growth\n- PMID:25278503 (Brown et al., 2014) — structure of human mitochondrial large subunit (includes MRPL28)\n- PMID:11551941 (Koc et al., 2001) — identification of 39S large subunit proteins including MRPL28\n- PMID:27023846 (Greber & Ban, 2016) — review of mitoribosome structure/function\n- PMID:34800366 (Morgenstern et al., 2021) — mitochondrial proteome including MRPL28\n- PMID:20186120 (Richter et al., 2010) — ICT1 in human mitoribosome\n- PMID:32877691 (Antonicka et al., 2020) — mitochondrial proximity network\n- PMID:26344197 (Wan et al., 2015) — metazoan complexes\n- PMID:22939629 (Havugimana et al., 2012) — protein complexes\n- Various interactome papers (BioPlex etc.) that identify MRPL28 as part of the mitoribosome\n\nThe key mechanistic paper is PMID:19753307 (Chen et al., 2009).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MRPL28 was identified as a protein component of the human mitochondrial large ribosomal subunit (39S subunit), established as a homolog of bacterial ribosomal protein L28 and confirmed by mass spectrometry peptide sequencing of purified 39S subunits.\",\n      \"method\": \"Proteolytic digestion of purified 39S subunits followed by LC-MS/MS peptide sequencing and database searching\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical identification from purified mitoribosome; foundational proteomics study establishing 39S composition\",\n      \"pmids\": [\"11551941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Knockdown of MRPL28 in pancreatic tumor cells decreased mitochondrial activity (oxidative phosphorylation) and increased compensatory glycolysis, but paradoxically decreased cellular growth in vitro while accelerating tumor growth in vivo, demonstrating that MRPL28 loss modulates the Warburg effect by reducing mitochondrial oxygen consumption and thereby relieving a rate-limiting constraint on tumor proliferation.\",\n      \"method\": \"shRNA knockdown of MRPL28 in pancreatic cancer cells; measurement of oxygen consumption, glycolysis, in vitro growth assays, and in vivo xenograft tumor growth assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific phenotypic readouts (O2 consumption, glycolysis, in vitro vs in vivo growth); single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"19753307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cryo-EM structure of the human mitochondrial large ribosomal subunit at 3.4 Å resolution revealed MRPL28 as one of 48 proteins in the 39S subunit, establishing its structural position within the mitoribosome and showing extensive remodeling relative to bacterial ribosomes, with the large subunit specialized for translating hydrophobic membrane proteins.\",\n      \"method\": \"Single-particle cryo-electron microscopy at 3.4 Å resolution\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with near-atomic resolution defining subunit composition and architecture\",\n      \"pmids\": [\"25278503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPL28 is a structural protein component of the 39S large subunit of the human mitochondrial ribosome (confirmed by proteomics and cryo-EM), where it contributes to mitochondrial translation of membrane proteins; its loss reduces mitochondrial oxidative phosphorylation and increases glycolysis, and in tumor cells this reduction in oxygen consumption paradoxically accelerates in vivo tumor growth by relieving oxygen as a rate-limiting substrate.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MRPL28 is a structural component of the 39S large subunit of the human mitochondrial ribosome, identified by mass spectrometry of purified subunits and positioned within the complex by cryo-EM at 3.4 Å resolution as one of 48 proteins in the remodeled mammalian mitoribosome [PMID:11551941, PMID:25278503]. As part of the mitoribosome, MRPL28 contributes to mitochondrial translation of hydrophobic membrane proteins essential for oxidative phosphorylation; its knockdown in pancreatic cancer cells reduces oxygen consumption and shifts metabolism toward glycolysis, paradoxically accelerating xenograft tumor growth by relieving oxygen as a rate-limiting substrate for proliferation [PMID:19753307].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The identity of MRPL28 as a bona fide subunit of the human 39S mitoribosomal large subunit was established, resolving the composition of the mammalian mitoribosome and assigning MRPL28 as the homolog of bacterial L28.\",\n      \"evidence\": \"LC-MS/MS peptide sequencing of purified human 39S subunits\",\n      \"pmids\": [\"11551941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural context for where MRPL28 sits within the 39S subunit\",\n        \"Functional contribution of MRPL28 to translation not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"MRPL28 loss was shown to impair mitochondrial oxidative phosphorylation and increase glycolysis, linking mitoribosomal function to metabolic reprogramming and demonstrating that reduced oxygen consumption can paradoxically promote tumor growth in vivo.\",\n      \"evidence\": \"shRNA knockdown in pancreatic cancer cells with oxygen consumption, glycolysis, and xenograft growth measurements\",\n      \"pmids\": [\"19753307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell line and lab; not independently replicated\",\n        \"Whether MRPL28 knockdown specifically impairs translation of particular mitochondrial mRNAs was not assessed\",\n        \"Mechanism by which reduced oxygen consumption accelerates in vivo growth (e.g., angiogenesis independence vs. diffusion advantage) was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Near-atomic cryo-EM resolved MRPL28's structural position within the 39S subunit, confirming it as an integral part of the extensively remodeled mammalian mitoribosome specialized for membrane protein translation.\",\n      \"evidence\": \"Single-particle cryo-EM of the human 39S subunit at 3.4 Å resolution\",\n      \"pmids\": [\"25278503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific protein–protein or protein–rRNA contacts mediated by MRPL28 not individually characterized\",\n        \"Whether MRPL28 is required for ribosome assembly vs. translation catalysis is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether MRPL28 plays a dedicated role in mitoribosome assembly, translational fidelity, or substrate selectivity beyond serving as a structural subunit, and whether its loss phenocopies other 39S subunit deficiencies in human disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No patient mutations or Mendelian disease link reported\",\n        \"No reconstitution or mutagenesis studies dissecting MRPL28-specific contacts\",\n        \"Role in mitoribosome assembly pathway not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"39S mitoribosomal large subunit\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}