{"gene":"TOMM6","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1998,"finding":"Tom6 (yeast) functions as an assembly factor for the TOM general import pore (GIP) complex: in mitochondria lacking Tom6, the interaction between Tom22 and Tom40 is destabilized, causing dissociation of Tom22 and generation of a ~100K subcomplex of Tom40, Tom7, and Tom5. Tom6 is required to promote but not to maintain the stable Tom22–Tom40 association.","method":"Yeast deletion mutant analysis, sucrose-gradient fractionation, immunoprecipitation of TOM complex components","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined biochemical phenotype, replicated in multiple TOM complex studies across labs","pmids":["9774667"],"is_preprint":false},{"year":1998,"finding":"Tom40 dynamically interacts with Tom6 during preprotein translocation; Tom40 exists in a homo-oligomeric assembly and the Tom40 assembly is influenced by Tom6, as shown by cross-linking and native complex analysis in both Neurospora crassa and S. cerevisiae.","method":"Chemical cross-linking, sucrose gradient sedimentation, native complex analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-linking and fractionation in two organisms, multiple labs","pmids":["9710610"],"is_preprint":false},{"year":1996,"finding":"Tom6 and Tom7 perform complementary and opposing functions in modulating TOM complex dynamics: Tom6 stabilizes the interaction between receptors (Tom20, Tom22) and Tom40, while Tom7 destabilizes it. Synthetic growth defects in tom7Δ tom6Δ double mutants provide genetic evidence for their functional relationship.","method":"Yeast deletion genetics, double-mutant epistasis analysis, protein import assays, immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double mutant lethality) combined with biochemical import assays, replicated in subsequent studies","pmids":["8641278"],"is_preprint":false},{"year":1999,"finding":"Tom6 is a constituent of the TOM core complex of Neurospora crassa (together with Tom40, Tom22, and Tom7), which forms a double-ring structure with two open pores (~2.1 nm diameter) that exhibits high-conductance channel activity and binds preprotein in a targeting sequence-dependent manner.","method":"Detergent solubilization, TOM core complex purification, electron tomography, planar lipid bilayer electrophysiology, preprotein binding assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural reconstruction combined with functional reconstitution; replicated across multiple labs","pmids":["10579717"],"is_preprint":false},{"year":2001,"finding":"Tom6 associates with a 100 kDa intermediate during the multistep assembly of the Tom40-containing GIP complex; this 100 kDa intermediate (Tom40 + Tom5) acquires Tom6 before maturation to the 400 kDa complex, identifying Tom6 as an early-stage assembly factor for Tom40 biogenesis.","method":"Radiolabeled precursor import assays, sucrose gradient sedimentation, native gel electrophoresis in yeast","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined sequential assembly intermediates with multiple orthogonal methods; replicated across labs","pmids":["11276259"],"is_preprint":false},{"year":2001,"finding":"Tom6 (Neurospora crassa) is in direct contact with Tom40 (by cross-linking) and interacts with Tom22 in a manner dependent on the presence of transiting preproteins. The targeting and assembly information of Tom6 resides in its transmembrane segment and a flanking N-terminal cytosolic segment; both segments are required for assembly into the TOM complex.","method":"Chemical cross-linking, in vitro import/assembly assays, domain-swap hybrid protein analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct cross-linking and mutagenesis/domain-swap experiments establishing topology and interaction requirements","pmids":["11278536"],"is_preprint":false},{"year":2001,"finding":"Tom40 and Tom22 together form the functional core unit of the GIP complex that stably retains accumulated preproteins; under stringent detergent conditions, Tom20 and all three small Tom proteins (including Tom6) are released while the preprotein remains in the Tom40–Tom22 core, demonstrating that Tom6 is dispensable for holding preproteins once import is initiated.","method":"Detergent fractionation, urea/salt treatment of arrested import intermediates, purified outer membrane vesicle import assays, electrophysiology","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods, reconstituted system","pmids":["11259583"],"is_preprint":false},{"year":2009,"finding":"During Tom40 biogenesis, the SAM-Tom5/Tom40 subcomplex binds the precursor of Tom6 after Tom6 has been inserted into the outer membrane in an Mim1-dependent manner, identifying Tom6 assembly as downstream of Mim1-mediated membrane insertion and dependent on the SAM complex.","method":"Co-immunoprecipitation of assembly intermediates, BN-PAGE, genetic deletion analysis (SAM subunit and Mim1 mutants) in yeast","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of assembly intermediates and genetic epistasis; replicated across labs","pmids":["20026336"],"is_preprint":false},{"year":2009,"finding":"Tom6 and Sam37 are functionally linked by genetic interaction: overexpression of TOM6 suppresses sam37Δ growth defects; overexpression of SAM37 suppresses tom6Δ; double deletion (tom6Δ sam37Δ) is lethal. Tom6 suppression of sam37Δ is linked to Tom6's ability to stabilize Tom40.","method":"Multicopy suppressor screen, yeast genetic analysis (single and double deletions), protein stability assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (synthetic lethality + suppression) with biochemical mechanistic follow-up","pmids":["19797086"],"is_preprint":false},{"year":2010,"finding":"Tom6 plays a stimulatory role at an early stage of Tom40 assembly at the SAM complex, antagonistic to Tom7's inhibitory role; Tom5 and Tom6 together promote formation of the mature TOM complex, while Tom7 opposes both Tom5 and Tom6 at this early assembly step.","method":"Yeast genetic deletion analysis, BN-PAGE, radiolabeled precursor import and assembly assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined epistatic relationships at sequential assembly steps using multiple genetic/biochemical methods","pmids":["21059357"],"is_preprint":false},{"year":2014,"finding":"Cell-cycle-dependent regulation of TOM complex assembly involves Cdk1-mediated phosphorylation of the cytosolic precursor of Tom6: cyclin Clb3-activated Cdk1 phosphorylates Tom6, enhancing its import into mitochondria, promoting Tom40 assembly and import of fusion proteins, and stimulating mitochondrial respiratory activity in mitosis.","method":"In vivo phosphorylation assays, cyclin-Cdk1 kinase assay, import assays with phospho-mimetic/phospho-null Tom6 mutants, mitochondrial respiratory measurements","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase assay identifying the writer (Cdk1/Clb3), mutagenesis of phosphorylation site, functional import assay, and physiological readout","pmids":["25378463"],"is_preprint":false},{"year":2017,"finding":"Cryo-EM structure of the TOM core complex from Neurospora crassa at near-atomic resolution shows Tom6 as one of three α-helical small subunits (alongside Tom5 and Tom7) surrounding each Tom40 β-barrel pore, contributing to the architecture of the symmetrical dimeric complex.","method":"Single-particle cryo-electron microscopy, structural modeling","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with direct assignment of Tom6 transmembrane helix position","pmids":["28802041"],"is_preprint":false},{"year":2019,"finding":"Cell-cycle-dependent variation of phosphorylated Tom6 modulates the trimeric TOM complex: phospho-Tom6 arising from Cdk1 activity promotes Tom22 integration into the TOM complex; porin Por1 sequesters Tom22 dissociated from trimeric TOM, and this sequestration is enhanced by the cell-cycle-controlled variation of phosphorylated Tom6, linking Tom6 phosphorylation state to TOM complex trimer/dimer equilibrium.","method":"Co-immunoprecipitation, BN-PAGE, in vivo cell-cycle synchronization, phospho-mimetic Tom6 mutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic/phospho-mimetic mutants, mechanistic link to TOM complex stoichiometry","pmids":["30738703"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of the dimeric human TOM core complex shows that Tom6 is one of three small α-helical subunits surrounding the Tom40 β-barrel channels; Tom6 has a notable configuration contributing to the overall architecture and the electrostatic features of the complex.","method":"Single-particle cryo-electron microscopy, structural modeling","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure of human TOM complex with direct visualization of Tom6","pmids":["33083003"],"is_preprint":false},{"year":2008,"finding":"Small Tom proteins including Tom6 (along with Tom22, Tom7, and Tom5) act as modulators of TOM pore dynamics; isolated Tom40 alone (without these subunits) shows no transitions between conductance states at low voltages, whereas the full TOM core complex (containing Tom6) displays robust gating, indicating Tom6 and other small Toms reduce the energy barrier between conformational states.","method":"Planar lipid bilayer electrophysiology comparing purified Tom40 alone vs. TOM core complex","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological comparison of Tom40 alone vs. TOM core complex, but Tom6's individual contribution not isolated from other small Toms","pmids":["18456827"],"is_preprint":false},{"year":2024,"finding":"In the human TOM holo complex structure, Tom6 stabilizes Tom20 through extensive interactions with Tom22, Tom40, and Tom6 itself; Tom20 is positioned at the center of the complex, stabilized in part by Tom6 contacts.","method":"Chemical cross-linking to stabilize Tom20, single-particle cryo-electron microscopy (~6 Å resolution)","journal":"PNAS nexus","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural visualization at moderate resolution (~6 Å); single study, Tom6 role inferred from structural contacts","pmids":["39071881"],"is_preprint":false},{"year":2025,"finding":"PP2A (protein phosphatase 2A), via its regulatory subunit Cdc55, dephosphorylates Ser16 of Tom6 in vitro. Synthetic trap-peptides enriched PP2A and PP4 as full holoenzymes from yeast cytosolic fractions, identifying PP2A as the first phosphatase (eraser) acting on TOM complex phosphorylation.","method":"Synthetic trap-peptide phosphatase enrichment from yeast cytosol, in vitro dephosphorylation assay with purified PP2A holoenzyme, mass spectrometry identification of regulatory subunits","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic (dephosphorylation) assay with identification of specific phosphatase and regulatory subunit; single lab but direct biochemical evidence","pmids":["40891445"],"is_preprint":false},{"year":2025,"finding":"In an Alzheimer disease model, aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 and promotes mitochondrial dysfunction; neuron-specific restoration of TOMM6 expression reduced beta-amyloid plaques but increased soluble beta-amyloid, indicating TOMM6 participates in a GRK2 aggregation-driven mitochondrial dysfunction pathway.","method":"Transgenic mouse AD model, neuronal TOMM6 overexpression, beta-amyloid quantification, mitochondrial function assays","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype with TOMM6 restoration in vivo, single study, pathway placement somewhat indirect","pmids":["41895286"],"is_preprint":false},{"year":2025,"finding":"Luteolin attenuates vascular calcification via the NF-κB/TOM6/PINK1 mitophagy axis: NF-κB drives TOM6 transcription; TOM6 knockdown attenuates calcification while overexpression exacerbates it; luteolin inhibits NF-κB nuclear translocation (by binding IKKα/IKKβ), suppresses TOM6 expression, and thereby enhances PINK1/Parkin-mediated mitophagy and improves mitochondrial bioenergetics.","method":"RNA sequencing, siRNA knockdown and overexpression of TOMM6 in vascular smooth muscle cells, in vivo mouse/rat calcification models, molecular docking (luteolin–IKK), Western blotting for mitophagy markers","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotypic readout, pathway placement by RNA-seq and mechanistic follow-up; single lab","pmids":["41232657"],"is_preprint":false},{"year":2011,"finding":"Tom6 facilitates mitochondrial mRNA localization in a transcript-specific manner: OXA1 mRNA (but not ATP2 mRNA) was mislocalized in tom6Δ yeast cells, suggesting Tom6 contributes to the localization of specific mRNAs to mitochondria.","method":"Live-cell fluorescence imaging of endogenously tagged mRNAs in tom6Δ yeast, quantitative colocalization analysis","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct in vivo localization assay with genetic deletion; effect is transcript-specific and single lab","pmids":["21705432"],"is_preprint":false},{"year":2025,"finding":"The Drosophila melanogaster TOM complex structure at 3.3 Å shows Tom6 as one of four endogenous TOM components (Tom22, Tom5, Tom6, Tom7) co-assembled with transgenic Tom40; the Drosophila and human TOM structures are very similar, with small conformational differences at subunit interfaces attributable to lipid-binding residue variation.","method":"Single-particle cryo-electron microscopy of ex vivo Drosophila TOM complex","journal":"IUCrJ","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution structure but limited mechanistic insight specific to Tom6 function beyond structural position; single study","pmids":["39575538"],"is_preprint":false}],"current_model":"TOMM6 (Tom6) is a small α-helical transmembrane subunit of the TOM core complex of the mitochondrial outer membrane that functions primarily as an assembly and stability factor: it promotes stable integration of Tom22 into the Tom40-containing general import pore, stimulates Tom40 assembly at the SAM complex, and modulates TOM complex dynamics in opposition to Tom7; its import efficiency and TOM complex stoichiometry are directly regulated by reversible phosphorylation—Cdk1/cyclin Clb3 phosphorylates Tom6 in a cell-cycle-dependent manner to enhance its mitochondrial import and TOM trimer formation, while PP2A (via regulatory subunit Cdc55) dephosphorylates Ser16 of Tom6, completing the regulatory cycle."},"narrative":{"mechanistic_narrative":"TOMM6 (Tom6) is a small α-helical transmembrane subunit of the mitochondrial outer-membrane TOM (translocase of the outer membrane) core complex, where it functions principally as an assembly and stability factor for the general import pore rather than as a component of the translocation channel itself [PMID:9774667, PMID:10579717]. Within the complex, Tom6 is one of three small α-helical subunits (with Tom5 and Tom7) that surround each Tom40 β-barrel pore, a position confirmed in cryo-EM structures of the fungal, human, and Drosophila TOM complexes [PMID:28802041, PMID:33083003, PMID:39575538]. Tom6 makes direct contact with Tom40 and engages Tom22 in a preprotein-dependent manner, promoting—but not maintaining—the stable Tom22–Tom40 association required for a functional pore; in its absence Tom22 dissociates and a Tom40/Tom7/Tom5 subcomplex accumulates [PMID:9774667, PMID:11278536]. During Tom40 biogenesis, Tom6 is inserted into the outer membrane in an Mim1-dependent step and is then acquired by a SAM-bound Tom40/Tom5 intermediate, where it acts early to stimulate Tom40 assembly in direct antagonism to the inhibitory small subunit Tom7 [PMID:11276259, PMID:20026336, PMID:21059357]. Tom6 and Tom7 thus exert opposing influences on TOM complex dynamics, stabilizing versus destabilizing receptor–channel interactions [PMID:8641278]. Tom6 abundance and TOM stoichiometry are controlled by reversible phosphorylation: Clb3-activated Cdk1 phosphorylates the cytosolic Tom6 precursor to enhance its mitochondrial import, drive Tom22 integration and TOM trimer formation, and boost respiratory activity in a cell-cycle-dependent manner, while PP2A (via its Cdc55 regulatory subunit) dephosphorylates Ser16 to reverse this regulation [PMID:25378463, PMID:30738703, PMID:40891445]. In human disease models TOMM6 has been linked to mitochondrial dysfunction, participating in a GRK2 aggregation pathway in Alzheimer disease and in an NF-κB/TOM6/PINK1 mitophagy axis driving vascular calcification [PMID:41895286, PMID:41232657].","teleology":[{"year":1996,"claim":"Established that the small TOM subunits are not redundant but functionally opposed, with Tom6 stabilizing and Tom7 destabilizing receptor–channel interactions.","evidence":"Yeast double-mutant epistasis (synthetic growth defect) plus import assays and immunoprecipitation","pmids":["8641278"],"confidence":"High","gaps":["Did not resolve the molecular basis of opposing dynamics","Did not separate assembly defects from steady-state pore function"]},{"year":1998,"claim":"Defined Tom6 as an assembly factor that promotes but does not maintain the stable Tom22–Tom40 association of the import pore, distinguishing assembly from channel function.","evidence":"Yeast deletion analysis with sucrose-gradient fractionation and immunoprecipitation of TOM components","pmids":["9774667","9710610"],"confidence":"High","gaps":["Mechanism by which Tom6 promotes Tom22 docking not defined","Did not address dynamics during active translocation"]},{"year":1999,"claim":"Placed Tom6 structurally within a purified, channel-active TOM core complex, confirming it as a bona fide constituent of the import pore.","evidence":"TOM core complex purification, electron tomography, and lipid-bilayer electrophysiology in Neurospora","pmids":["10579717"],"confidence":"High","gaps":["Low-resolution architecture only","Individual contribution of Tom6 to channel properties not isolated"]},{"year":2001,"claim":"Resolved the sequential assembly pathway, identifying Tom6 as an early-stage factor that joins a Tom40/Tom5 intermediate, and mapped the topological determinants for its own assembly.","evidence":"Radiolabeled precursor import/assembly assays, native gels, cross-linking, and domain-swap mutagenesis in yeast and Neurospora","pmids":["11276259","11278536","11259583"],"confidence":"High","gaps":["Order of small-Tom incorporation relative to receptors not fully resolved","Did not identify membrane insertion machinery"]},{"year":2009,"claim":"Connected Tom6 assembly to the broader outer-membrane biogenesis machinery, showing Mim1-dependent insertion upstream and SAM-dependent acquisition during Tom40 maturation.","evidence":"Co-IP of assembly intermediates, BN-PAGE, and genetic deletion of SAM subunits and Mim1; multicopy suppressor genetics with SAM37","pmids":["20026336","19797086"],"confidence":"High","gaps":["Direct physical Tom6–Mim1 interaction not demonstrated","Functional overlap with Sam37 mechanistically unresolved"]},{"year":2010,"claim":"Quantified the antagonism at the SAM assembly step, defining Tom5/Tom6 as stimulatory and Tom7 as inhibitory for mature TOM formation.","evidence":"Yeast genetic deletion, BN-PAGE, and radiolabeled precursor assembly assays","pmids":["21059357"],"confidence":"High","gaps":["Structural basis of stimulation vs inhibition unknown","Kinetics of competing reactions not measured"]},{"year":2014,"claim":"Revealed that TOM assembly is dynamically regulated by the cell cycle through Cdk1/Clb3 phosphorylation of the Tom6 precursor, coupling mitochondrial import capacity to mitosis.","evidence":"Cyclin-Cdk1 kinase assays, phospho-mutant import assays, and mitochondrial respiratory measurements","pmids":["25378463"],"confidence":"High","gaps":["Did not identify the dephosphorylating enzyme","Conservation of regulation in humans not tested"]},{"year":2019,"claim":"Mechanistically linked Tom6 phosphorylation state to TOM trimer/dimer equilibrium via Tom22 integration and Por1-mediated sequestration of dissociated Tom22.","evidence":"Co-IP, BN-PAGE, cell-cycle synchronization, and phospho-mimetic Tom6 mutants","pmids":["30738703"],"confidence":"High","gaps":["Stoichiometric details of Por1–Tom22 sequestration unresolved","Physiological output of trimer vs dimer not fully defined"]},{"year":2020,"claim":"Provided atomic-resolution placement of Tom6 in the human TOM core complex, establishing structural conservation of its position around the Tom40 barrel.","evidence":"Single-particle cryo-EM of the dimeric human TOM core complex; complemented by Neurospora (2017) and Drosophila (2025) structures","pmids":["33083003","28802041","39575538"],"confidence":"High","gaps":["Cytosolic precursor/phospho-regulated states not captured","Dynamic conformational transitions not resolved"]},{"year":2024,"claim":"Extended Tom6's role to receptor stabilization, showing it helps position and stabilize Tom20 within the holo complex.","evidence":"Cross-linking to trap Tom20 followed by ~6 Å cryo-EM of the human TOM holo complex","pmids":["39071881"],"confidence":"Medium","gaps":["Moderate resolution; Tom6–Tom20 role inferred from contacts","Single study, not functionally validated"]},{"year":2025,"claim":"Identified PP2A/Cdc55 as the eraser that dephosphorylates Tom6 Ser16, completing the writer–eraser regulatory cycle of TOM phosphorylation.","evidence":"Synthetic trap-peptide phosphatase enrichment and in vitro dephosphorylation with purified PP2A holoenzyme; MS identification of regulatory subunits","pmids":["40891445"],"confidence":"High","gaps":["In vivo cell-cycle role of PP2A on Tom6 not demonstrated","Single lab; specificity over other substrates not bounded"]},{"year":2025,"claim":"Implicated TOMM6 in mammalian disease pathways, linking it to GRK2-driven mitochondrial dysfunction in Alzheimer models and to an NF-κB/TOM6/PINK1 mitophagy axis in vascular calcification.","evidence":"Transgenic AD mouse with neuronal TOMM6 restoration; RNA-seq plus siRNA/overexpression in vascular smooth muscle cells with in vivo calcification models","pmids":["41895286","41232657"],"confidence":"Medium","gaps":["Pathway placement is indirect","Whether disease roles reflect TOM-import function or other activity unclear","Single study per disease context"]},{"year":2011,"claim":"Suggested a role for Tom6 beyond protein import, in transcript-specific mitochondrial mRNA localization.","evidence":"Live-cell imaging of endogenously tagged mRNAs in tom6Δ yeast","pmids":["21705432"],"confidence":"Medium","gaps":["Transcript-specific effect mechanistically unexplained","Single lab; relationship to import function unknown"]},{"year":null,"claim":"Whether the Cdk1/PP2A phosphorylation cycle that governs Tom6-dependent TOM dynamics in yeast operates in mammalian cells, and how it intersects with the disease-associated mitophagy and aggregation pathways, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Human regulatory writer/eraser for TOMM6 not identified","Mechanistic link between TOM assembly regulation and disease phenotypes unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,9,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,15]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,10]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,7,9]}],"complexes":["TOM core complex","TOM holo complex"],"partners":["TOMM40","TOMM22","TOMM7","TOMM5","TOMM20","SAM37","MIM1","POR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96B49","full_name":"Mitochondrial import receptor subunit TOM6 homolog","aliases":["Overexpressed breast tumor protein","Translocase of outer membrane 6 kDa subunit homolog"],"length_aa":74,"mass_kda":8.0,"function":"Component of the translocase of the outer membrane of mitochondria (TOM) complex essential for the recognition and translocation of cytosolically synthesized mitochondrial preproteins (PubMed:40080546). The TOM complex associates with the ion channel VDAC2 and PINK1 kinase at depolarized mitochondria, this interaction stabilizes PINK1 at the outer mitochondrial membrane and triggers downstream mitophagy by the recruitment of the E3 ubiquitin ligase PRKN (PubMed:40080546)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q96B49/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOMM6","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TOMM6","total_profiled":1310},"omim":[{"mim_id":"616169","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 5; TOMM5","url":"https://www.omim.org/entry/616169"},{"mim_id":"616168","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 6; TOMM6","url":"https://www.omim.org/entry/616168"},{"mim_id":"607980","title":"TRANSLOCASE OF OUTER MITOCHONDRIAL MEMBRANE 7; TOMM7","url":"https://www.omim.org/entry/607980"}],"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/TOMM6"},"hgnc":{"alias_symbol":["OBTP","Tom6"],"prev_symbol":[]},"alphafold":{"accession":"Q96B49","domains":[{"cath_id":"1.20.5","chopping":"30-62","consensus_level":"high","plddt":81.1133,"start":30,"end":62}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B49","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B49-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96B49-F1-predicted_aligned_error_v6.png","plddt_mean":70.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOMM6","jax_strain_url":"https://www.jax.org/strain/search?query=TOMM6"},"sequence":{"accession":"Q96B49","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96B49.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96B49/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96B49"}},"corpus_meta":[{"pmid":"9774667","id":"PMC_9774667","title":"Preprotein translocase of the outer mitochondrial membrane: molecular dissection and assembly of the general import pore complex.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9774667","citation_count":212,"is_preprint":false},{"pmid":"10579717","id":"PMC_10579717","title":"The TOM core complex: the general protein import pore of the outer membrane of mitochondria.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10579717","citation_count":173,"is_preprint":false},{"pmid":"11276259","id":"PMC_11276259","title":"Multistep assembly of the protein import channel of the mitochondrial outer membrane.","date":"2001","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/11276259","citation_count":165,"is_preprint":false},{"pmid":"11259583","id":"PMC_11259583","title":"Protein import channel of the outer mitochondrial membrane: a highly stable Tom40-Tom22 core structure differentially interacts with preproteins, small tom proteins, and import receptors.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11259583","citation_count":147,"is_preprint":false},{"pmid":"28802041","id":"PMC_28802041","title":"Cryo-EM Structure of the TOM Core Complex from Neurospora crassa.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/28802041","citation_count":142,"is_preprint":false},{"pmid":"11402060","id":"PMC_11402060","title":"Tom40, the pore-forming component of the protein-conducting TOM channel in the outer membrane of mitochondria.","date":"2001","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11402060","citation_count":141,"is_preprint":false},{"pmid":"8641278","id":"PMC_8641278","title":"Tom7 modulates the dynamics of the mitochondrial outer membrane translocase and plays a pathway-related role in protein import.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8641278","citation_count":137,"is_preprint":false},{"pmid":"25378463","id":"PMC_25378463","title":"Mitochondria. 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Tom6 is required to promote but not to maintain the stable Tom22–Tom40 association.\",\n      \"method\": \"Yeast deletion mutant analysis, sucrose-gradient fractionation, immunoprecipitation of TOM complex components\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined biochemical phenotype, replicated in multiple TOM complex studies across labs\",\n      \"pmids\": [\"9774667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Tom40 dynamically interacts with Tom6 during preprotein translocation; Tom40 exists in a homo-oligomeric assembly and the Tom40 assembly is influenced by Tom6, as shown by cross-linking and native complex analysis in both Neurospora crassa and S. cerevisiae.\",\n      \"method\": \"Chemical cross-linking, sucrose gradient sedimentation, native complex analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-linking and fractionation in two organisms, multiple labs\",\n      \"pmids\": [\"9710610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Tom6 and Tom7 perform complementary and opposing functions in modulating TOM complex dynamics: Tom6 stabilizes the interaction between receptors (Tom20, Tom22) and Tom40, while Tom7 destabilizes it. Synthetic growth defects in tom7Δ tom6Δ double mutants provide genetic evidence for their functional relationship.\",\n      \"method\": \"Yeast deletion genetics, double-mutant epistasis analysis, protein import assays, immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double mutant lethality) combined with biochemical import assays, replicated in subsequent studies\",\n      \"pmids\": [\"8641278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Tom6 is a constituent of the TOM core complex of Neurospora crassa (together with Tom40, Tom22, and Tom7), which forms a double-ring structure with two open pores (~2.1 nm diameter) that exhibits high-conductance channel activity and binds preprotein in a targeting sequence-dependent manner.\",\n      \"method\": \"Detergent solubilization, TOM core complex purification, electron tomography, planar lipid bilayer electrophysiology, preprotein binding assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural reconstruction combined with functional reconstitution; replicated across multiple labs\",\n      \"pmids\": [\"10579717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tom6 associates with a 100 kDa intermediate during the multistep assembly of the Tom40-containing GIP complex; this 100 kDa intermediate (Tom40 + Tom5) acquires Tom6 before maturation to the 400 kDa complex, identifying Tom6 as an early-stage assembly factor for Tom40 biogenesis.\",\n      \"method\": \"Radiolabeled precursor import assays, sucrose gradient sedimentation, native gel electrophoresis in yeast\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined sequential assembly intermediates with multiple orthogonal methods; replicated across labs\",\n      \"pmids\": [\"11276259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tom6 (Neurospora crassa) is in direct contact with Tom40 (by cross-linking) and interacts with Tom22 in a manner dependent on the presence of transiting preproteins. The targeting and assembly information of Tom6 resides in its transmembrane segment and a flanking N-terminal cytosolic segment; both segments are required for assembly into the TOM complex.\",\n      \"method\": \"Chemical cross-linking, in vitro import/assembly assays, domain-swap hybrid protein analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct cross-linking and mutagenesis/domain-swap experiments establishing topology and interaction requirements\",\n      \"pmids\": [\"11278536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Tom40 and Tom22 together form the functional core unit of the GIP complex that stably retains accumulated preproteins; under stringent detergent conditions, Tom20 and all three small Tom proteins (including Tom6) are released while the preprotein remains in the Tom40–Tom22 core, demonstrating that Tom6 is dispensable for holding preproteins once import is initiated.\",\n      \"method\": \"Detergent fractionation, urea/salt treatment of arrested import intermediates, purified outer membrane vesicle import assays, electrophysiology\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods, reconstituted system\",\n      \"pmids\": [\"11259583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"During Tom40 biogenesis, the SAM-Tom5/Tom40 subcomplex binds the precursor of Tom6 after Tom6 has been inserted into the outer membrane in an Mim1-dependent manner, identifying Tom6 assembly as downstream of Mim1-mediated membrane insertion and dependent on the SAM complex.\",\n      \"method\": \"Co-immunoprecipitation of assembly intermediates, BN-PAGE, genetic deletion analysis (SAM subunit and Mim1 mutants) in yeast\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of assembly intermediates and genetic epistasis; replicated across labs\",\n      \"pmids\": [\"20026336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tom6 and Sam37 are functionally linked by genetic interaction: overexpression of TOM6 suppresses sam37Δ growth defects; overexpression of SAM37 suppresses tom6Δ; double deletion (tom6Δ sam37Δ) is lethal. Tom6 suppression of sam37Δ is linked to Tom6's ability to stabilize Tom40.\",\n      \"method\": \"Multicopy suppressor screen, yeast genetic analysis (single and double deletions), protein stability assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (synthetic lethality + suppression) with biochemical mechanistic follow-up\",\n      \"pmids\": [\"19797086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tom6 plays a stimulatory role at an early stage of Tom40 assembly at the SAM complex, antagonistic to Tom7's inhibitory role; Tom5 and Tom6 together promote formation of the mature TOM complex, while Tom7 opposes both Tom5 and Tom6 at this early assembly step.\",\n      \"method\": \"Yeast genetic deletion analysis, BN-PAGE, radiolabeled precursor import and assembly assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined epistatic relationships at sequential assembly steps using multiple genetic/biochemical methods\",\n      \"pmids\": [\"21059357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cell-cycle-dependent regulation of TOM complex assembly involves Cdk1-mediated phosphorylation of the cytosolic precursor of Tom6: cyclin Clb3-activated Cdk1 phosphorylates Tom6, enhancing its import into mitochondria, promoting Tom40 assembly and import of fusion proteins, and stimulating mitochondrial respiratory activity in mitosis.\",\n      \"method\": \"In vivo phosphorylation assays, cyclin-Cdk1 kinase assay, import assays with phospho-mimetic/phospho-null Tom6 mutants, mitochondrial respiratory measurements\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase assay identifying the writer (Cdk1/Clb3), mutagenesis of phosphorylation site, functional import assay, and physiological readout\",\n      \"pmids\": [\"25378463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cryo-EM structure of the TOM core complex from Neurospora crassa at near-atomic resolution shows Tom6 as one of three α-helical small subunits (alongside Tom5 and Tom7) surrounding each Tom40 β-barrel pore, contributing to the architecture of the symmetrical dimeric complex.\",\n      \"method\": \"Single-particle cryo-electron microscopy, structural modeling\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with direct assignment of Tom6 transmembrane helix position\",\n      \"pmids\": [\"28802041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cell-cycle-dependent variation of phosphorylated Tom6 modulates the trimeric TOM complex: phospho-Tom6 arising from Cdk1 activity promotes Tom22 integration into the TOM complex; porin Por1 sequesters Tom22 dissociated from trimeric TOM, and this sequestration is enhanced by the cell-cycle-controlled variation of phosphorylated Tom6, linking Tom6 phosphorylation state to TOM complex trimer/dimer equilibrium.\",\n      \"method\": \"Co-immunoprecipitation, BN-PAGE, in vivo cell-cycle synchronization, phospho-mimetic Tom6 mutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic/phospho-mimetic mutants, mechanistic link to TOM complex stoichiometry\",\n      \"pmids\": [\"30738703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of the dimeric human TOM core complex shows that Tom6 is one of three small α-helical subunits surrounding the Tom40 β-barrel channels; Tom6 has a notable configuration contributing to the overall architecture and the electrostatic features of the complex.\",\n      \"method\": \"Single-particle cryo-electron microscopy, structural modeling\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure of human TOM complex with direct visualization of Tom6\",\n      \"pmids\": [\"33083003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Small Tom proteins including Tom6 (along with Tom22, Tom7, and Tom5) act as modulators of TOM pore dynamics; isolated Tom40 alone (without these subunits) shows no transitions between conductance states at low voltages, whereas the full TOM core complex (containing Tom6) displays robust gating, indicating Tom6 and other small Toms reduce the energy barrier between conformational states.\",\n      \"method\": \"Planar lipid bilayer electrophysiology comparing purified Tom40 alone vs. TOM core complex\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological comparison of Tom40 alone vs. TOM core complex, but Tom6's individual contribution not isolated from other small Toms\",\n      \"pmids\": [\"18456827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the human TOM holo complex structure, Tom6 stabilizes Tom20 through extensive interactions with Tom22, Tom40, and Tom6 itself; Tom20 is positioned at the center of the complex, stabilized in part by Tom6 contacts.\",\n      \"method\": \"Chemical cross-linking to stabilize Tom20, single-particle cryo-electron microscopy (~6 Å resolution)\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural visualization at moderate resolution (~6 Å); single study, Tom6 role inferred from structural contacts\",\n      \"pmids\": [\"39071881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PP2A (protein phosphatase 2A), via its regulatory subunit Cdc55, dephosphorylates Ser16 of Tom6 in vitro. Synthetic trap-peptides enriched PP2A and PP4 as full holoenzymes from yeast cytosolic fractions, identifying PP2A as the first phosphatase (eraser) acting on TOM complex phosphorylation.\",\n      \"method\": \"Synthetic trap-peptide phosphatase enrichment from yeast cytosol, in vitro dephosphorylation assay with purified PP2A holoenzyme, mass spectrometry identification of regulatory subunits\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic (dephosphorylation) assay with identification of specific phosphatase and regulatory subunit; single lab but direct biochemical evidence\",\n      \"pmids\": [\"40891445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an Alzheimer disease model, aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 and promotes mitochondrial dysfunction; neuron-specific restoration of TOMM6 expression reduced beta-amyloid plaques but increased soluble beta-amyloid, indicating TOMM6 participates in a GRK2 aggregation-driven mitochondrial dysfunction pathway.\",\n      \"method\": \"Transgenic mouse AD model, neuronal TOMM6 overexpression, beta-amyloid quantification, mitochondrial function assays\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype with TOMM6 restoration in vivo, single study, pathway placement somewhat indirect\",\n      \"pmids\": [\"41895286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Luteolin attenuates vascular calcification via the NF-κB/TOM6/PINK1 mitophagy axis: NF-κB drives TOM6 transcription; TOM6 knockdown attenuates calcification while overexpression exacerbates it; luteolin inhibits NF-κB nuclear translocation (by binding IKKα/IKKβ), suppresses TOM6 expression, and thereby enhances PINK1/Parkin-mediated mitophagy and improves mitochondrial bioenergetics.\",\n      \"method\": \"RNA sequencing, siRNA knockdown and overexpression of TOMM6 in vascular smooth muscle cells, in vivo mouse/rat calcification models, molecular docking (luteolin–IKK), Western blotting for mitophagy markers\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotypic readout, pathway placement by RNA-seq and mechanistic follow-up; single lab\",\n      \"pmids\": [\"41232657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tom6 facilitates mitochondrial mRNA localization in a transcript-specific manner: OXA1 mRNA (but not ATP2 mRNA) was mislocalized in tom6Δ yeast cells, suggesting Tom6 contributes to the localization of specific mRNAs to mitochondria.\",\n      \"method\": \"Live-cell fluorescence imaging of endogenously tagged mRNAs in tom6Δ yeast, quantitative colocalization analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct in vivo localization assay with genetic deletion; effect is transcript-specific and single lab\",\n      \"pmids\": [\"21705432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Drosophila melanogaster TOM complex structure at 3.3 Å shows Tom6 as one of four endogenous TOM components (Tom22, Tom5, Tom6, Tom7) co-assembled with transgenic Tom40; the Drosophila and human TOM structures are very similar, with small conformational differences at subunit interfaces attributable to lipid-binding residue variation.\",\n      \"method\": \"Single-particle cryo-electron microscopy of ex vivo Drosophila TOM complex\",\n      \"journal\": \"IUCrJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution structure but limited mechanistic insight specific to Tom6 function beyond structural position; single study\",\n      \"pmids\": [\"39575538\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOMM6 (Tom6) is a small α-helical transmembrane subunit of the TOM core complex of the mitochondrial outer membrane that functions primarily as an assembly and stability factor: it promotes stable integration of Tom22 into the Tom40-containing general import pore, stimulates Tom40 assembly at the SAM complex, and modulates TOM complex dynamics in opposition to Tom7; its import efficiency and TOM complex stoichiometry are directly regulated by reversible phosphorylation—Cdk1/cyclin Clb3 phosphorylates Tom6 in a cell-cycle-dependent manner to enhance its mitochondrial import and TOM trimer formation, while PP2A (via regulatory subunit Cdc55) dephosphorylates Ser16 of Tom6, completing the regulatory cycle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOMM6 (Tom6) is a small α-helical transmembrane subunit of the mitochondrial outer-membrane TOM (translocase of the outer membrane) core complex, where it functions principally as an assembly and stability factor for the general import pore rather than as a component of the translocation channel itself [#0, #3]. Within the complex, Tom6 is one of three small α-helical subunits (with Tom5 and Tom7) that surround each Tom40 β-barrel pore, a position confirmed in cryo-EM structures of the fungal, human, and Drosophila TOM complexes [#11, #13, #20]. Tom6 makes direct contact with Tom40 and engages Tom22 in a preprotein-dependent manner, promoting—but not maintaining—the stable Tom22–Tom40 association required for a functional pore; in its absence Tom22 dissociates and a Tom40/Tom7/Tom5 subcomplex accumulates [#0, #5]. During Tom40 biogenesis, Tom6 is inserted into the outer membrane in an Mim1-dependent step and is then acquired by a SAM-bound Tom40/Tom5 intermediate, where it acts early to stimulate Tom40 assembly in direct antagonism to the inhibitory small subunit Tom7 [#4, #7, #9]. Tom6 and Tom7 thus exert opposing influences on TOM complex dynamics, stabilizing versus destabilizing receptor–channel interactions [#2]. Tom6 abundance and TOM stoichiometry are controlled by reversible phosphorylation: Clb3-activated Cdk1 phosphorylates the cytosolic Tom6 precursor to enhance its mitochondrial import, drive Tom22 integration and TOM trimer formation, and boost respiratory activity in a cell-cycle-dependent manner, while PP2A (via its Cdc55 regulatory subunit) dephosphorylates Ser16 to reverse this regulation [#10, #12, #16]. In human disease models TOMM6 has been linked to mitochondrial dysfunction, participating in a GRK2 aggregation pathway in Alzheimer disease and in an NF-κB/TOM6/PINK1 mitophagy axis driving vascular calcification [#17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the small TOM subunits are not redundant but functionally opposed, with Tom6 stabilizing and Tom7 destabilizing receptor–channel interactions.\",\n      \"evidence\": \"Yeast double-mutant epistasis (synthetic growth defect) plus import assays and immunoprecipitation\",\n      \"pmids\": [\"8641278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular basis of opposing dynamics\", \"Did not separate assembly defects from steady-state pore function\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined Tom6 as an assembly factor that promotes but does not maintain the stable Tom22–Tom40 association of the import pore, distinguishing assembly from channel function.\",\n      \"evidence\": \"Yeast deletion analysis with sucrose-gradient fractionation and immunoprecipitation of TOM components\",\n      \"pmids\": [\"9774667\", \"9710610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Tom6 promotes Tom22 docking not defined\", \"Did not address dynamics during active translocation\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed Tom6 structurally within a purified, channel-active TOM core complex, confirming it as a bona fide constituent of the import pore.\",\n      \"evidence\": \"TOM core complex purification, electron tomography, and lipid-bilayer electrophysiology in Neurospora\",\n      \"pmids\": [\"10579717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low-resolution architecture only\", \"Individual contribution of Tom6 to channel properties not isolated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the sequential assembly pathway, identifying Tom6 as an early-stage factor that joins a Tom40/Tom5 intermediate, and mapped the topological determinants for its own assembly.\",\n      \"evidence\": \"Radiolabeled precursor import/assembly assays, native gels, cross-linking, and domain-swap mutagenesis in yeast and Neurospora\",\n      \"pmids\": [\"11276259\", \"11278536\", \"11259583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of small-Tom incorporation relative to receptors not fully resolved\", \"Did not identify membrane insertion machinery\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected Tom6 assembly to the broader outer-membrane biogenesis machinery, showing Mim1-dependent insertion upstream and SAM-dependent acquisition during Tom40 maturation.\",\n      \"evidence\": \"Co-IP of assembly intermediates, BN-PAGE, and genetic deletion of SAM subunits and Mim1; multicopy suppressor genetics with SAM37\",\n      \"pmids\": [\"20026336\", \"19797086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical Tom6–Mim1 interaction not demonstrated\", \"Functional overlap with Sam37 mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantified the antagonism at the SAM assembly step, defining Tom5/Tom6 as stimulatory and Tom7 as inhibitory for mature TOM formation.\",\n      \"evidence\": \"Yeast genetic deletion, BN-PAGE, and radiolabeled precursor assembly assays\",\n      \"pmids\": [\"21059357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of stimulation vs inhibition unknown\", \"Kinetics of competing reactions not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed that TOM assembly is dynamically regulated by the cell cycle through Cdk1/Clb3 phosphorylation of the Tom6 precursor, coupling mitochondrial import capacity to mitosis.\",\n      \"evidence\": \"Cyclin-Cdk1 kinase assays, phospho-mutant import assays, and mitochondrial respiratory measurements\",\n      \"pmids\": [\"25378463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the dephosphorylating enzyme\", \"Conservation of regulation in humans not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistically linked Tom6 phosphorylation state to TOM trimer/dimer equilibrium via Tom22 integration and Por1-mediated sequestration of dissociated Tom22.\",\n      \"evidence\": \"Co-IP, BN-PAGE, cell-cycle synchronization, and phospho-mimetic Tom6 mutants\",\n      \"pmids\": [\"30738703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometric details of Por1–Tom22 sequestration unresolved\", \"Physiological output of trimer vs dimer not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided atomic-resolution placement of Tom6 in the human TOM core complex, establishing structural conservation of its position around the Tom40 barrel.\",\n      \"evidence\": \"Single-particle cryo-EM of the dimeric human TOM core complex; complemented by Neurospora (2017) and Drosophila (2025) structures\",\n      \"pmids\": [\"33083003\", \"28802041\", \"39575538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytosolic precursor/phospho-regulated states not captured\", \"Dynamic conformational transitions not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended Tom6's role to receptor stabilization, showing it helps position and stabilize Tom20 within the holo complex.\",\n      \"evidence\": \"Cross-linking to trap Tom20 followed by ~6 Å cryo-EM of the human TOM holo complex\",\n      \"pmids\": [\"39071881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Moderate resolution; Tom6–Tom20 role inferred from contacts\", \"Single study, not functionally validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified PP2A/Cdc55 as the eraser that dephosphorylates Tom6 Ser16, completing the writer–eraser regulatory cycle of TOM phosphorylation.\",\n      \"evidence\": \"Synthetic trap-peptide phosphatase enrichment and in vitro dephosphorylation with purified PP2A holoenzyme; MS identification of regulatory subunits\",\n      \"pmids\": [\"40891445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cell-cycle role of PP2A on Tom6 not demonstrated\", \"Single lab; specificity over other substrates not bounded\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated TOMM6 in mammalian disease pathways, linking it to GRK2-driven mitochondrial dysfunction in Alzheimer models and to an NF-κB/TOM6/PINK1 mitophagy axis in vascular calcification.\",\n      \"evidence\": \"Transgenic AD mouse with neuronal TOMM6 restoration; RNA-seq plus siRNA/overexpression in vascular smooth muscle cells with in vivo calcification models\",\n      \"pmids\": [\"41895286\", \"41232657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement is indirect\", \"Whether disease roles reflect TOM-import function or other activity unclear\", \"Single study per disease context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Suggested a role for Tom6 beyond protein import, in transcript-specific mitochondrial mRNA localization.\",\n      \"evidence\": \"Live-cell imaging of endogenously tagged mRNAs in tom6Δ yeast\",\n      \"pmids\": [\"21705432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcript-specific effect mechanistically unexplained\", \"Single lab; relationship to import function unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the Cdk1/PP2A phosphorylation cycle that governs Tom6-dependent TOM dynamics in yeast operates in mammalian cells, and how it intersects with the disease-associated mitophagy and aggregation pathways, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human regulatory writer/eraser for TOMM6 not identified\", \"Mechanistic link between TOM assembly regulation and disease phenotypes unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 9, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 7, 9]}\n    ],\n    \"complexes\": [\"TOM core complex\", \"TOM holo complex\"],\n    \"partners\": [\"TOMM40\", \"TOMM22\", \"TOMM7\", \"TOMM5\", \"TOMM20\", \"SAM37\", \"MIM1\", \"POR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}