{"gene":"TIMM17B","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2024,"finding":"TIMM17B is a core subunit of the human TIM23 presequence translocase of the inner mitochondrial membrane. Computational structural modeling (AlphaFold-based tools) predicts that TIMM17B forms a complex with TIMM23 and ROMO1 (a homolog of yeast Mgr2) that is highly structurally conserved with the yeast Tim17/Tim23 core, with TIMM17B-containing TIM23 being one of two distinct human TIM23 variants. Both TIMM17A- and TIMM17B-containing variants show similar architecture, and ROMO1 is predicted to create a channel-like structure with TIMM17B analogous to yeast Mgr2/Tim17.","method":"Computational structural prediction (AlphaFold2/ColabFold) with comparative structural analysis against yeast TIM23 complex; functional inference from conservation","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental structural or biochemical validation reported in the abstract","pmids":["38837610"],"is_preprint":false},{"year":2024,"finding":"The prohibitin complex (PHB1/PHB2) is required to stabilize both TIMM17A- and TIMM17B-containing variants of the human TIM23 translocase. OCIAD1 assembles with the prohibitin complex specifically to protect the TIMM17A variant (not TIMM17B) from degradation by the YME1L protease, and OCIAD1 expression is itself regulated by the status of the TIM23 complex, constituting a regulatory axis that differentially regulates the two TIM23 variants.","method":"Co-immunoprecipitation, knockdown/knockout of OCIAD1 and prohibitins, protease inhibition assays, blue-native PAGE to assess TIM23 complex integrity, quantitative proteomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO/KD with defined molecular phenotype, multiple orthogonal methods (native PAGE, quantitative MS, protease assays) in a single focused study","pmids":["39630581"],"is_preprint":false},{"year":2025,"finding":"Manipulation of TIMM17B expression (as well as TIMM17A or TIMM23) in human cells decreases import of proteins into mitochondria, establishing that TIMM17B is required for efficient mitochondrial protein import in intact human cells. This was demonstrated using the mitoRUSH (retention using selective hooks) pulse-chase assay and a complementary nascent-protein labeling method with amino acid analog and click chemistry.","method":"mitoRUSH (RUSH-based pulse-chase import assay), nascent protein labeling with non-canonical amino acid analog (azidohomoalanine) and click chemistry, siRNA-mediated knockdown of TIMM17B in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal import assays in intact human cells, single lab, with defined functional phenotype (reduced mitochondrial protein import) upon TIMM17B knockdown","pmids":["40631992"],"is_preprint":false}],"current_model":"TIMM17B is a core subunit of one of two distinct human TIM23 presequence translocase variants in the inner mitochondrial membrane, required for efficient import of nuclear-encoded proteins into the mitochondrial matrix; its stability within the TIM23 complex is maintained by the prohibitin complex, while the paralog TIMM17A (but not TIMM17B) is additionally protected from YME1L-mediated degradation by OCIAD1."},"narrative":{"mechanistic_narrative":"TIMM17B is a core subunit of the human TIM23 presequence translocase in the inner mitochondrial membrane, where it is required for efficient import of nuclear-encoded proteins into mitochondria [PMID:40631992]. Knockdown of TIMM17B in intact human cells reduces mitochondrial protein import, as measured by orthogonal pulse-chase (mitoRUSH) and nascent-protein labeling assays [PMID:40631992]. The stability of the TIMM17B-containing TIM23 complex is maintained by the prohibitin (PHB1/PHB2) complex; in contrast to the paralogous TIMM17A variant, the TIMM17B variant is not protected from YME1L protease degradation by OCIAD1, defining a regulatory axis that differentially controls the two TIM23 variants [PMID:39630581]. Beyond these findings, structural and biochemical detail of the TIMM17B translocase has not been experimentally characterized in the available corpus.","teleology":[{"year":2024,"claim":"Whether human TIM23 contains a distinct TIMM17B-based variant and how it is organized was unclear; comparative modeling established TIMM17B as a core subunit of one of two human TIM23 translocase variants conserved with the yeast Tim17/Tim23 core.","evidence":"AlphaFold2/ColabFold structural prediction with comparative analysis against the yeast TIM23 complex","pmids":["38837610"],"confidence":"Low","gaps":["Computational prediction only, no experimental structural or biochemical validation","Channel-like ROMO1/TIMM17B architecture not confirmed in vitro","Functional distinction between TIMM17A and TIMM17B variants not addressed"]},{"year":2024,"claim":"How the two TIM23 variants are stabilized and differentially regulated was unknown; this work showed the prohibitin complex stabilizes both variants while OCIAD1 specifically shields the TIMM17A (not TIMM17B) variant from YME1L degradation.","evidence":"Reciprocal Co-IP, OCIAD1/prohibitin KO/KD, protease inhibition, blue-native PAGE and quantitative proteomics in human cells","pmids":["39630581"],"confidence":"High","gaps":["Mechanism of how OCIAD1 selectively distinguishes TIMM17A from TIMM17B is not resolved","Physiological consequence of losing TIMM17B-variant stability not defined","Whether prohibitin acts directly or via membrane organization is unresolved"]},{"year":2025,"claim":"Whether TIMM17B is functionally required for import in living human cells (rather than predicted) was open; depletion experiments established that TIMM17B is needed for efficient mitochondrial protein import.","evidence":"mitoRUSH pulse-chase import assay and azidohomoalanine/click nascent-protein labeling with siRNA knockdown in human cells","pmids":["40631992"],"confidence":"Medium","gaps":["Substrate selectivity of the TIMM17B versus TIMM17A variant not defined","Single-lab demonstration","Does not resolve which precursor classes depend on TIMM17B"]},{"year":null,"claim":"It remains unknown whether the TIMM17B-containing translocase imports a distinct substrate repertoire from the TIMM17A variant and what the physiological role of variant specialization is.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No substrate-resolved comparison of the two variants","No experimental structure of the human TIMM17B translocase","Tissue/condition-specific roles of TIMM17B unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2]}],"complexes":["TIM23 presequence translocase"],"partners":["TIMM23","ROMO1","PHB1","PHB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60830","full_name":"Mitochondrial import inner membrane translocase subunit Tim17-B","aliases":[],"length_aa":172,"mass_kda":18.3,"function":"Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/O60830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TIMM17B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOMM20A","stoichiometry":10.0},{"gene":"HEATR3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TIMM17B","total_profiled":1310},"omim":[{"mim_id":"605057","title":"TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 17A; TIMM17A","url":"https://www.omim.org/entry/605057"},{"mim_id":"605034","title":"TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 23; TIMM23","url":"https://www.omim.org/entry/605034"},{"mim_id":"300249","title":"TRANSLOCASE OF INNER MITOCHONDRIAL MEMBRANE 17B; TIMM17B","url":"https://www.omim.org/entry/300249"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TIMM17B"},"hgnc":{"alias_symbol":["DXS9822","JM3"],"prev_symbol":[]},"alphafold":{"accession":"O60830","domains":[{"cath_id":"-","chopping":"8-86","consensus_level":"medium","plddt":93.8861,"start":8,"end":86},{"cath_id":"-","chopping":"88-128","consensus_level":"medium","plddt":95.8532,"start":88,"end":128}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60830","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60830-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60830-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TIMM17B","jax_strain_url":"https://www.jax.org/strain/search?query=TIMM17B"},"sequence":{"accession":"O60830","fasta_url":"https://rest.uniprot.org/uniprotkb/O60830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60830"}},"corpus_meta":[{"pmid":"20162231","id":"PMC_20162231","title":"Measuring the local pressure amplitude in microchannel acoustophoresis.","date":"2010","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/20162231","citation_count":144,"is_preprint":false},{"pmid":"8419930","id":"PMC_8419930","title":"Nitrilase in biosynthesis of the plant hormone indole-3-acetic acid from indole-3-acetonitrile: cloning of the Alcaligenes gene and site-directed mutagenesis of cysteine residues.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8419930","citation_count":109,"is_preprint":false},{"pmid":"15001443","id":"PMC_15001443","title":"Single cell mechanics of rat cardiomyocytes under isometric, unloaded, and physiologically loaded conditions.","date":"2004","source":"American journal of physiology. 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radiation on the nucleic acid synthesis rate in proliferating and resting cells].","date":"1983","source":"Tsitologiia","url":"https://pubmed.ncbi.nlm.nih.gov/6197795","citation_count":4,"is_preprint":false},{"pmid":"26263697","id":"PMC_26263697","title":"[Activated Sludge Bacteria Transforming Cyanopyridines and Amides of Pyridinecarboxylic Acids].","date":"2015","source":"Mikrobiologiia","url":"https://pubmed.ncbi.nlm.nih.gov/26263697","citation_count":3,"is_preprint":false},{"pmid":"10099297","id":"PMC_10099297","title":"The effects of turbulent jet flows on plant cell suspension cultures.","date":"1998","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/10099297","citation_count":3,"is_preprint":false},{"pmid":"40631992","id":"PMC_40631992","title":"MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.","date":"2025","source":"Journal of cell 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gelatin for protein delivery applications.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40419052","citation_count":1,"is_preprint":false},{"pmid":"40222321","id":"PMC_40222321","title":"A multiaxial bioreactor system that applies targeted magnitudes of strain energy to 3D cellular constructs.","date":"2025","source":"Journal of the mechanical behavior of biomedical materials","url":"https://pubmed.ncbi.nlm.nih.gov/40222321","citation_count":1,"is_preprint":false},{"pmid":"41639056","id":"PMC_41639056","title":"Engineering thin 3D Li-composite foil negative electrodes with high mechanical toughness.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41639056","citation_count":1,"is_preprint":false},{"pmid":"6215555","id":"PMC_6215555","title":"A monoclonal antibody that binds preferentially to human suppressor T cells.","date":"1982","source":"Microbiology and 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40761308","citation_count":0,"is_preprint":false},{"pmid":"41214948","id":"PMC_41214948","title":"Optimizing quality and palatability in texture-modified foods: A cross-framework study using sweet potato-based formulations.","date":"2025","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/41214948","citation_count":0,"is_preprint":false},{"pmid":"41700836","id":"PMC_41700836","title":"Distortion Energy Drives Cellular and Mechanical Changes in Fibroblast-Seeded Collagen Scaffolds Under Cyclic Loading.","date":"2026","source":"Journal of biomechanical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/41700836","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.02.605684","title":"The phage protein paratox is a multifunctional metabolic regulator of  <i>Streptococcus</i>","date":"2024-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.02.605684","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21620,"output_tokens":1586,"usd":0.044325,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7543,"output_tokens":1572,"usd":0.038508,"stage2_stop_reason":"end_turn"},"total_usd":0.082833,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries about TIMM17B (aliases: DXS9822, JM3).\n\n**Classification analysis:**\n- Papers [1]-[6], [8]-[11], [13]-[14], [16], [18], [21]-[24], [26]-[28], [30]-[34], [39]-[40]: Irrelevant (physics, materials science, microbiology enzymes, plant biology, etc.)\n- Papers [2], [4], [13], [27]: About *Alcaligenes faecalis* JM3 nitrilase — \"JM3\" here is a bacterial strain name, not the TIMM17B alias\n- Papers [35], [37]: JM3-3-3A is a monoclonal antibody clone name, not the gene\n- Paper [36], [41]: JM3 = phage protein SpyM3_1246 in *Streptococcus* — symbol collision, not the human gene\n- Paper [25]: JM1/JM2/JM3 = IA-2 epitope designations — not the gene\n- Paper [9]: JM2, JM3 = mink lung cell lines — not the gene\n- Paper [38]: Mentions TIMM17B in context of chromosomal deletion causing Renpenning syndrome — clinical/genetic, no mechanistic experiment on TIMM17B function\n- Paper [7]: GWAS association study — no mechanistic experiment\n- Paper [12]: Expression downregulation in heart failure — no mechanistic experiment\n- Paper [15]: TIMM17B used as reference gene for qPCR normalization — no mechanistic content\n- Paper [17]: TIMM17B listed as predicted miR-146b-5p target — expression/bioinformatics\n- Paper [19]: **RELEVANT** — OCIAD1 and prohibitins regulate TIM23 stability, specifically addressing TIMM17A and TIMM17B variants\n- Paper [20]: **RELEVANT** — Structure prediction of human core TIM23 complex with TIMM17A/TIMM17B\n- Paper [29]: **RELEVANT** — mitoRUSH assay, TIMM17B manipulation affects mitochondrial protein import\n- Paper [31]: TIMM17B listed as downregulated DEG — transcriptomic, no mechanistic experiment\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"TIMM17B is a core subunit of the human TIM23 presequence translocase of the inner mitochondrial membrane. Computational structural modeling (AlphaFold-based tools) predicts that TIMM17B forms a complex with TIMM23 and ROMO1 (a homolog of yeast Mgr2) that is highly structurally conserved with the yeast Tim17/Tim23 core, with TIMM17B-containing TIM23 being one of two distinct human TIM23 variants. Both TIMM17A- and TIMM17B-containing variants show similar architecture, and ROMO1 is predicted to create a channel-like structure with TIMM17B analogous to yeast Mgr2/Tim17.\",\n      \"method\": \"Computational structural prediction (AlphaFold2/ColabFold) with comparative structural analysis against yeast TIM23 complex; functional inference from conservation\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental structural or biochemical validation reported in the abstract\",\n      \"pmids\": [\"38837610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The prohibitin complex (PHB1/PHB2) is required to stabilize both TIMM17A- and TIMM17B-containing variants of the human TIM23 translocase. OCIAD1 assembles with the prohibitin complex specifically to protect the TIMM17A variant (not TIMM17B) from degradation by the YME1L protease, and OCIAD1 expression is itself regulated by the status of the TIM23 complex, constituting a regulatory axis that differentially regulates the two TIM23 variants.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/knockout of OCIAD1 and prohibitins, protease inhibition assays, blue-native PAGE to assess TIM23 complex integrity, quantitative proteomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO/KD with defined molecular phenotype, multiple orthogonal methods (native PAGE, quantitative MS, protease assays) in a single focused study\",\n      \"pmids\": [\"39630581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Manipulation of TIMM17B expression (as well as TIMM17A or TIMM23) in human cells decreases import of proteins into mitochondria, establishing that TIMM17B is required for efficient mitochondrial protein import in intact human cells. This was demonstrated using the mitoRUSH (retention using selective hooks) pulse-chase assay and a complementary nascent-protein labeling method with amino acid analog and click chemistry.\",\n      \"method\": \"mitoRUSH (RUSH-based pulse-chase import assay), nascent protein labeling with non-canonical amino acid analog (azidohomoalanine) and click chemistry, siRNA-mediated knockdown of TIMM17B in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal import assays in intact human cells, single lab, with defined functional phenotype (reduced mitochondrial protein import) upon TIMM17B knockdown\",\n      \"pmids\": [\"40631992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIMM17B is a core subunit of one of two distinct human TIM23 presequence translocase variants in the inner mitochondrial membrane, required for efficient import of nuclear-encoded proteins into the mitochondrial matrix; its stability within the TIM23 complex is maintained by the prohibitin complex, while the paralog TIMM17A (but not TIMM17B) is additionally protected from YME1L-mediated degradation by OCIAD1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIMM17B is a core subunit of the human TIM23 presequence translocase in the inner mitochondrial membrane, where it is required for efficient import of nuclear-encoded proteins into mitochondria [#2]. Knockdown of TIMM17B in intact human cells reduces mitochondrial protein import, as measured by orthogonal pulse-chase (mitoRUSH) and nascent-protein labeling assays [#2]. The stability of the TIMM17B-containing TIM23 complex is maintained by the prohibitin (PHB1/PHB2) complex; in contrast to the paralogous TIMM17A variant, the TIMM17B variant is not protected from YME1L protease degradation by OCIAD1, defining a regulatory axis that differentially controls the two TIM23 variants [#1]. Beyond these findings, structural and biochemical detail of the TIMM17B translocase has not been experimentally characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether human TIM23 contains a distinct TIMM17B-based variant and how it is organized was unclear; comparative modeling established TIMM17B as a core subunit of one of two human TIM23 translocase variants conserved with the yeast Tim17/Tim23 core.\",\n      \"evidence\": \"AlphaFold2/ColabFold structural prediction with comparative analysis against the yeast TIM23 complex\",\n      \"pmids\": [\"38837610\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no experimental structural or biochemical validation\", \"Channel-like ROMO1/TIMM17B architecture not confirmed in vitro\", \"Functional distinction between TIMM17A and TIMM17B variants not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How the two TIM23 variants are stabilized and differentially regulated was unknown; this work showed the prohibitin complex stabilizes both variants while OCIAD1 specifically shields the TIMM17A (not TIMM17B) variant from YME1L degradation.\",\n      \"evidence\": \"Reciprocal Co-IP, OCIAD1/prohibitin KO/KD, protease inhibition, blue-native PAGE and quantitative proteomics in human cells\",\n      \"pmids\": [\"39630581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how OCIAD1 selectively distinguishes TIMM17A from TIMM17B is not resolved\", \"Physiological consequence of losing TIMM17B-variant stability not defined\", \"Whether prohibitin acts directly or via membrane organization is unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether TIMM17B is functionally required for import in living human cells (rather than predicted) was open; depletion experiments established that TIMM17B is needed for efficient mitochondrial protein import.\",\n      \"evidence\": \"mitoRUSH pulse-chase import assay and azidohomoalanine/click nascent-protein labeling with siRNA knockdown in human cells\",\n      \"pmids\": [\"40631992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity of the TIMM17B versus TIMM17A variant not defined\", \"Single-lab demonstration\", \"Does not resolve which precursor classes depend on TIMM17B\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the TIMM17B-containing translocase imports a distinct substrate repertoire from the TIMM17A variant and what the physiological role of variant specialization is.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate-resolved comparison of the two variants\", \"No experimental structure of the human TIMM17B translocase\", \"Tissue/condition-specific roles of TIMM17B unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"TIM23 presequence translocase\"],\n    \"partners\": [\"TIMM23\", \"ROMO1\", \"PHB1\", \"PHB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}