Falcon deep research report for TOMM40
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Falcon corroborates TOMM40 as the beta-barrel TOM complex pore in the mitochondrial outer membrane and separates this core import function from less direct APOE-region disease association signals.
"**Primary molecular function:** Tom40 (TOMM40 product) is a **β‑barrel translocation pore** in the mitochondrial outer membrane that enables **import of nuclear-encoded mitochondrial precursor proteins** into mitochondria as part of the TOM complex."
Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on curation of immunofluorescence data
Characterization of rat TOM40, a central component of the preprotein translocase of the mitochondrial outer membrane.
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Mammalian Tom40 is embedded in the mitochondrial outer membrane likely as a beta-barrel, lacking predicted alpha-helical transmembrane segments.
"Although it has no predictable alpha-helical transmembrane segments, OM38 is resistant to alkaline carbonate extraction and is inaccessible to proteases and polyclonal antibodies added from outside the mitochondria, suggesting that it is embedded in the membrane, probably in a beta-barrel structure"
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Tom40 is a component of an ~400-kDa TOM complex, firmly associating with Tom22 and with the import receptor Tom20.
"Blue native polyacrylamide gel electrophoresis revealed that OM38 is a component of a approximately 400-kDa complex, firmly associating with rTOM22 and loosely associating with rTOM20."
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Tom40 is essential for preprotein import activity of the mitochondrial outer membrane.
"The preprotein in transit to the matrix interacted with the TOM complex containing OM38, and immunodepletion of OM38 resulted in the loss of preprotein import activity of the detergent-solubilized and reconstituted outer membrane vesicles."
Genetic identity and differential expression of p38.5 (Haymaker) in human malignant and nonmalignant cells.
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Identifies the p38.5 (Haymaker) protein as the chromosome-19 gene product later recognized as TOMM40, with elevated expression in malignant cells.
"Sequence analyses of these cDNA clones reveal open reading frames (ORFs) that include the previously identified 11-mer peptide from purified, native p38.5 and that have identical sequences to a gene of unknown function on chromosome 19."
Insertion and assembly of human tom7 into the preprotein translocase complex of the outer mitochondrial membrane.
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In human mitochondria, newly imported Tom7 assembles into a ~120-kDa Tom40-containing intermediate that is chased into the mature ~380-kDa TOM complex upon addition of Tom22.
"We found that the 120-kDa complex contains Tom40 and lacks receptor components. This intermediate can be chased to the stable approximately 380-kDa mammalian TOM complex that additionally contains Tom22."
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Tom40 is the channel-forming core of the general import pore complex that translocates preproteins into mitochondria.
"Tom7 is a component of the translocase of the outer mitochondrial membrane (TOM) and assembles into a general import pore complex that translocates preproteins into mitochondria."
Dissection of the mitochondrial import and assembly pathway for human Tom40.
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TOMM40 is the channel-forming subunit of the human TOM complex and is essential for protein import into mitochondria.
"Tom40 is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM complex), essential for protein import into mitochondria."
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Hsp90 chaperones delivery of the Tom40 precursor to mitochondria in an ATP-dependent manner before its assembly via the TOM and SAM complexes.
"We identify that Hsp90 is involved in delivery of the Tom40 precursor to mitochondria in an ATP-dependent manner. The precursor then forms its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly."
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Efficient assembly of human Tom40 into the mature TOM complex requires the outer membrane SAM complex (Sam50).
"we show that Tom40 assembly is reduced in mitochondria depleted of human Sam50."
Identification of Tom5 and Tom6 in the preprotein translocase complex of human mitochondrial outer membrane.
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Human Tom40 is the central import channel of the TOM complex and small Tom5/Tom6/Tom7 subunits maintain the structural integrity of the complex.
"The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7"
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Depletion of TOMM40 in human cells reduces the steady-state levels of all small Tom subunits, indicating Tom40 is required for their stability in the TOM complex.
"Conversely, knockdown of hTom40 decreased the level of all small Tom proteins."
Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression.
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Cited in the context of mitochondrial respiration regulation; the study shows cyclin B1/Cdk1 phosphorylates mitochondrial complex I subunits in the matrix (not a direct TOMM40 function paper).
"a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain."
Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability.
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TOMM40 physically interacts with Tim29 to couple the outer-membrane TOM complex to the inner-membrane TIM22 carrier translocase in human mitochondria.
"Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane, TOM complex, enabling a mechanism for transport of hydrophobic carrier substrates across the aqueous intermembrane space."
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Chemical cross-linking and co-immunoprecipitation demonstrate a direct hTom40-Tim29 interaction that bridges the TIM22 and TOM complexes.
"we found hTom40 cross-linked to Tim29... these results suggest that Tim29 acts as a bridge between the TIM22 and TOM complexes."
BAP31 regulates mitochondrial function via interaction with Tom40 within ER-mitochondria contact sites.
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TOMM40 interacts with the ER membrane protein BAP31 at ER-mitochondria contact sites to facilitate import of the complex I subunit NDUFS4.
"BAP31 interacts with mitochondria-localized proteins, including Tom40, to stimulate the translocation of NDUFS4, the component of complex I from the cytosol to the mitochondria."
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Disruption of the BAP31-Tom40 bridging complex impairs mitochondrial complex I activity and oxygen consumption due to reduced NDUFS4 import.
"Disruption of the BAP31-Tom40 complex inhibits mitochondrial complex I activity and oxygen consumption by the decreased NDUFS4 localization to the mitochondria."
TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion.
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TOMM40 directly binds the autophagy lipid-transfer protein Atg2A via its C-terminal MAM localization domain, recruiting Atg2A to mitochondria- associated ER membranes during phagophore expansion.
"Proteomic analysis identifies the outer mitochondrial membrane protein TOM40 as a MLD-interacting partner. The Atg2A-TOM40 interaction is responsible for MAM localization of Atg2A and requires the TOM receptor protein TOM70."
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The TOM70-TOM40 complex recruits Atg2A to the MAM to enable lipid transfer for autophagosome expansion.
"we propose a model that the TOM70-TOM40 complex recruits Atg2A to the MAM for vesicular and/or non-vesicular lipid transport into the expanding phagophore to grow the size of autophagosomes for efficient autophagic flux."
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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TOMM40 is included in the high-confidence human mitochondrial proteome (MitoCoP), confirming its mitochondrial localization as a translocase subunit.
"We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). We identified interactors of translocases, respiratory chain, and ATP synthase assembly factors."
Pink1 is recruited from the cytoplasm to the mitochondria