Affinage

TRAP1

Putative endoplasmin-like protein · UniProt Q58FF3

Length
399 aa
Mass
45.9 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAP1 is a mitochondrial matrix Hsp90-family molecular chaperone with intrinsic, geldanamycin/radicicol-sensitive ATPase activity that functions as a metabolic regulator controlling the balance between oxidative phosphorylation and aerobic glycolysis (PMID:10652318, PMID:23564345, PMID:31987035). Unlike cytosolic Hsp90, it does not engage classical co-chaperones (p23, Hop) and cannot reconstitute steroid receptor folding, defining it as a functionally distinct chaperone (PMID:10652318); its principal quantitative interactors within the matrix are mtHSP70 and HSP60, and it assembles into dimers and stable tetramers whose abundance tracks OXPHOS state (PMID:31987035). TRAP1 suppresses mitochondrial respiration by directly binding and inhibiting respiratory components — succinate dehydrogenase and complex III via UQCRC2 — thereby restraining OXPHOS and reinforcing a glycolytic (Warburg) phenotype, an effect amplified through its interaction with and stabilization of phosphofructokinase-1 (PFK1) (PMID:28099845, PMID:33025742, PMID:36510251); loss of TRAP1 globally derepresses respiration and reroutes metabolism toward glutamine anaplerosis (PMID:25088416, PMID:31987035). TRAP1 expression is transcriptionally driven by HIF1α and Myc to enforce this metabolic program under hypoxic and oncogenic conditions (PMID:33934112, PMID:31097545). As a cytoprotective factor, TRAP1 acts downstream of the PINK1/HTRA2 axis — PINK1 binds and phosphorylates TRAP1 to block oxidative-stress-induced cytochrome c release and apoptosis, a function disrupted by Parkinson's-disease-linked PINK1 mutations (PMID:17579517, PMID:29050400), and TRAP1 inhibits cyclophilin D-dependent permeability transition pore opening by competing for the OSCP subunit of F-ATP synthase (PMID:35614131, PMID:26500047). Its chaperone cycle is allosterically tuned by Ca²⁺, which substitutes for Mg²⁺ to drive cooperative ATP hydrolysis, and by S-nitrosylation at Cys501, which lowers ATPase activity (PMID:32088262, PMID:29991590). Beyond the matrix, TRAP1 cooperates with the proteasomal regulatory subunit TBP7 to govern ubiquitination and stability of client proteins including CDK1, MAD2 and BRAF, linking it to cell-cycle control, and it modulates cap-dependent translation through eIF2α/PERK/GCN2 signaling (PMID:21979464, PMID:25239454, PMID:28678347, PMID:24113185). A TRAP1 loss-of-function mutation identified in a Parkinson's disease patient produced mitochondrial dysfunction, connecting the gene to neurodegeneration (PMID:29050400).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established TRAP1 as a mitochondrial matrix Hsp90-like ATPase that is nonetheless functionally distinct from cytosolic Hsp90, framing the core question of what a chaperone does inside mitochondria.

    Evidence Immunofluorescence, immunogold EM with mitochondrial subfractionation, in vitro ATPase and inhibitor assays, co-chaperone binding and receptor reconstitution

    PMID:10652318 PMID:11010808

    Open questions at the time
    • Did not identify matrix client proteins or substrates
    • Extramitochondrial sites observed but their functional meaning unresolved
  2. 2007 High

    Defined TRAP1 as a cytoprotective node downstream of the PINK1 kinase and an anti-ROS factor, connecting its chaperone activity to apoptosis suppression and Parkinson's disease genetics.

    Evidence Co-IP, in vitro and in vivo kinase assays, PD mutant analysis, GzmM cleavage and ROS/cytochrome c readouts with RNAi and overexpression

    PMID:17513296 PMID:17579517

    Open questions at the time
    • Phosphorylation sites and their structural consequences not mapped here
    • How phosphorylation alters chaperone clients unknown
  3. 2011 High

    Extended TRAP1 function beyond the matrix by showing it partners with the proteasomal subunit TBP7 in the ER to control ubiquitination and stability of client proteins, linking it to protein quality control.

    Evidence Mass spectrometry, Co-IP, confocal/EM, FRET, shRNA silencing with UPR marker readouts

    PMID:21338643 PMID:21979464

    Open questions at the time
    • Mechanism of TRAP1 ER targeting not defined
    • Direct vs indirect control of ubiquitination unresolved
  4. 2013 High

    Identified the central biological role of TRAP1 as a switch governing OXPHOS versus aerobic glycolysis, and placed it epistatically downstream of Pink1 in mitochondrial maintenance.

    Evidence TRAP1-null cells and Drosophila genetics, metabolic flux and Seahorse respirometry, c-Src Co-IP, ribosome/translation factor Co-IP and eIF2α phosphorylation

    PMID:23328674 PMID:23564345 PMID:24113185

    Open questions at the time
    • Direct respiratory targets not yet identified in these studies
    • Translation regulation mechanism (direct vs stress-induced) incomplete
  5. 2014 Medium

    Connected TRAP1 metabolic control to client-protein turnover (BRAF) and to organismal phenotypes, showing TRAP1 loss reduces age-associated pathology and tumor incidence while activating retrograde and UPRmt stress signaling.

    Evidence TRAP1 knockout mouse transcriptome/bioenergetics, ubiquitination and cell-cycle assays, Drosophila FOXO and Dve epistasis

    PMID:25088416 PMID:25239454 PMID:25265088 PMID:26631731

    Open questions at the time
    • Whether BRAF effect is via direct chaperoning unresolved
    • Retrograde signaling shown in flies, not mapped in mammals
  6. 2015 High

    Provided the structural basis for TRAP1 ATP hydrolysis and inhibitor binding, enabling mitochondria-targeted inhibitor design and confirming PTP-inhibitory cytoprotection in neural stem cells.

    Evidence X-ray crystallography of inhibitor and AMP-PNP complexes, structure-guided drug synthesis, mPTP and cytochrome c assays

    PMID:25785725 PMID:26500047

    Open questions at the time
    • Conformational cycle in physiological matrix context not captured
    • Client-binding region not localized in these structures
  7. 2016 Medium

    Linked TRAP1 to oncogenic signaling beyond metabolism by showing it maintains cancer stem cell stemness through Wnt/β-catenin regulation.

    Evidence siRNA knockdown, colony formation, β-catenin ubiquitination/phosphorylation Western blots, tumor IHC

    PMID:27662365

    Open questions at the time
    • Direct molecular link between matrix TRAP1 and cytosolic Wnt signaling unclear
    • Single-lab, single-tumor-type evidence
  8. 2017 High

    Resolved how TRAP1 is regulated and how it controls respiration and the cell cycle, showing ERK1/2 phosphorylation drives an SDH-inhibitory complex required for tumorigenicity, TBP7-dependent CDK1/MAD2 quality control gating G2-M, and HTRA2 regulation of TRAP1 levels.

    Evidence Co-IP, mitochondrial fractionation, site-directed mutagenesis, SDH activity, ubiquitination/rescue, mass spectrometry interactome, patient fibroblasts

    PMID:28099845 PMID:28678347 PMID:29050400

    Open questions at the time
    • Whether ERK1/2 phosphosites overlap PINK1 sites unknown
    • HTRA2 regulates TRAP1 by non-proteolytic mechanism not defined
  9. 2018 High

    Revealed Ca²⁺ as an allosteric cofactor that imposes cooperative ATP hydrolysis between TRAP1 protomers, linking mitochondrial calcium status to chaperone cycle kinetics.

    Evidence Anomalous X-ray diffraction identifying the Ca²⁺ site, in vitro ATPase with defined cations and cooperative kinetics

    PMID:29991590

    Open questions at the time
    • Physiological calcium concentrations driving this in vivo not established
    • Functional consequence for client handling untested
  10. 2020 High

    Defined TRAP1 quaternary structure, its core matrix interactors, and the precise mechanisms tuning its metabolic output, including ATPase-independent OXPHOS regulation, S-nitrosylation control, PFK1 stabilization, and allosteric/structure-based inhibition.

    Evidence Native gels, quantitative MS interactome, ATPase-dead and C501S mutants, computational allosteric pocket targeting, Co-IP, metabolomics, zebrafish

    PMID:31987035 PMID:32088262 PMID:32320652 PMID:33025742

    Open questions at the time
    • How tetramerization couples to client binding unresolved
    • S-nitrosylation regulation in vivo not demonstrated
  11. 2021 Medium

    Identified upstream transcriptional control of TRAP1 by HIF1α and Myc and localized a client-binding drug site in the middle domain, expanding the catalog of TRAP1 mitochondrial interactors.

    Evidence Promoter/ChIP analysis, HIF1α stabilization, genetic knockout, zebrafish respirometry, MitoQ structural and client-competition studies, MS interactome

    PMID:31097545 PMID:33934112 PMID:34758612

    Open questions at the time
    • Direct middle-domain client identities largely uncharacterized
    • Interplay between HIF1α and Myc induction not integrated
  12. 2022 High

    Established direct, reconstituted mechanisms by which TRAP1 controls the permeability transition pore and complex III, showing it competes with cyclophilin D at F-ATP synthase OSCP and binds UQCRC2 to set respiration.

    Evidence Electrophysiology of purified F-ATP synthase, competition binding, ATPase and complex III activity assays, Co-IP, membrane potential and cell death readouts

    PMID:35614131 PMID:36510251

    Open questions at the time
    • Stoichiometry of TRAP1 at OSCP not defined
    • How phosphorylation/nitrosylation feed into PTP control untested
  13. 2024 High

    Connected the TRAP1 glycolytic phenotype to an epigenetic disease mechanism, showing TRAP1-driven lactate causes histone lactylation that activates SASP genes and drives vascular smooth muscle senescence and atherosclerosis.

    Evidence VSMC-specific Trap1 knockout in ApoeKO mice, ChIP, lactylation and HDAC3 activity assays, senescence markers

    PMID:39088352

    Open questions at the time
    • Whether this mechanism generalizes beyond vascular cells unknown
    • Link to chaperone vs metabolic function not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • The matrix client repertoire that TRAP1 directly folds, and how its chaperone cycle mechanistically dictates the choice between protein quality control, respiratory complex inhibition, and PTP regulation, remains unresolved.
  • No comprehensive direct-client list with folding readouts
  • Causal hierarchy among metabolic, cell-cycle, and apoptotic roles undefined
  • Integration of multiple post-translational regulatory inputs (Ca²⁺, phosphorylation, S-nitrosylation) into a unified cycle not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140657 ATP-dependent activity 4 GO:0044183 protein folding chaperone 3 GO:0016787 hydrolase activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 1
Partners
CDK1HTRA2MTHSP70PFK1PINK1SORCINTBP7UQCRC2
Complex memberships
F-ATP synthase (OSCP)respiratory complex IIIsuccinate dehydrogenase (complex II)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TRAP1 is localized to the mitochondrial matrix, contains a mitochondrial targeting sequence at its N-terminus, binds ATP, and exhibits ATPase activity that is inhibited by geldanamycin and radicicol. TRAP1 does not form stable complexes with classic Hsp90 co-chaperones p23 and Hop, and cannot substitute for Hsp90 in progesterone receptor reconstitution assays, indicating distinct functional properties from Hsp90. Immunofluorescence, in vitro ATPase assay, geldanamycin/radicicol inhibition, co-chaperone binding assays, progesterone receptor reconstitution assay The Journal of biological chemistry High 10652318
2000 TRAP1 is primarily a mitochondrial matrix protein as determined by quantitative immunogold electron microscopy and Western blot of purified mitochondrial subfractions. TRAP1 also localizes to specific extramitochondrial sites including pancreatic zymogen granules, insulin secretory granules, cardiac sarcomeres, nuclei, and endothelial cell surfaces. Quantitative immunogold electron microscopy, Western blot of purified mitochondrial subfractions, immunofluorescence Experimental cell research High 11010808
2007 PINK1 kinase binds and co-localizes with TRAP1 in mitochondria, and phosphorylates TRAP1 both in vitro and in vivo. PINK1-mediated phosphorylation of TRAP1 is required for PINK1's protective action against oxidative-stress-induced cytochrome c release and cell death. PD-linked PINK1 mutations (G309D, L347P, W437X) impair TRAP1 phosphorylation and cell survival. Co-immunoprecipitation, co-localization, in vitro kinase assay, in vivo phosphorylation, siRNA/overexpression with cell death readout, PD mutant analysis PLoS biology High 17579517
2007 Granzyme M (GzmM) cleaves TRAP1 in the mitochondria, abolishing its antagonistic function against reactive oxygen species (ROS), leading to ROS accumulation and cytochrome c release. TRAP1 knockdown by RNAi increases ROS accumulation, while TRAP1 overexpression attenuates ROS production, identifying TRAP1 as an anti-ROS factor that protects cells from GzmM-mediated apoptosis. siRNA knockdown, overexpression, ROS measurement, cytochrome c release assay, cleavage assay The Journal of biological chemistry Medium 17513296
2011 TRAP1 interacts with and co-localizes with the 19S proteasomal subunit TBP7/Rpt3 in the endoplasmic reticulum (first demonstration of TRAP1 in ER), as confirmed by biochemical fractionation, confocal microscopy, electron microscopy, and FRET analysis. This TRAP1–TBP7 interaction controls ubiquitination and stability of specific nuclear-encoded mitochondrial proteins, and TRAP1 silencing correlates with upregulation of BiP/Grp78 under ER stress, implicating TRAP1 in ER protein quality control. Mass spectrometry, co-immunoprecipitation, confocal microscopy, electron microscopy, FRET, shRNA silencing, Western blot Cell death and differentiation High 21979464
2010 Sorcin, a Ca²⁺-binding protein, was identified as a TRAP1-interacting protein by proteomic analysis of TRAP1 co-immunoprecipitation complexes. A <20 kDa isoform of Sorcin localizes to mitochondria and specifically interacts with TRAP1. TRAP1 stability and Sorcin mitochondrial localization are mutually dependent: TRAP1 depletion reduces mitochondrial Sorcin, and Sorcin depletion increases TRAP1 degradation. Co-immunoprecipitation, mass spectrometry proteomics, shRNA/siRNA knockdown, fluorescence microscopy, Western blot of mitochondrial fractions Cancer research High 20647321
2013 TRAP1 regulates a metabolic switch between oxidative phosphorylation (OXPHOS) and aerobic glycolysis. TRAP1-deficiency promotes increased mitochondrial respiration, fatty acid oxidation, accumulation of TCA cycle intermediates, ATP, and ROS, while suppressing glucose metabolism. TRAP1 interaction with and regulation of mitochondrial c-Src provides a mechanistic basis for these metabolic phenotypes. TRAP1-null cells, siRNA silencing, overexpression, metabolic flux analysis, co-immunoprecipitation with c-Src, Seahorse respirometry Proceedings of the National Academy of Sciences of the United States of America High 23564345
2013 Drosophila Trap1 works downstream of Pink1 and in parallel with parkin in controlling mitochondrial function. Trap1 null mutants show decreased mitochondrial function and increased stress sensitivity. Overexpression of Trap1 in neurons rescues mitochondrial impairment in Pink1 mutant flies, and parkin overexpression rescues Trap1 mutant phenotypes (and vice versa), establishing epistatic relationships. Drosophila genetics, null mutants, overexpression rescue, mitochondrial function assays, epistasis analysis Cell death & disease High 23328674
2013 TRAP1 is associated with ribosomes and multiple translation factors in colon carcinoma cells, and regulates the rate of protein synthesis through the eIF2α pathway. TRAP1 favors activation of GCN2 and PERK kinases, leading to eIF2α phosphorylation and attenuation of cap-dependent translation, which enhances synthesis of stress-responsive proteins (ATF4, BiP/Grp78, xCT). Ribosome co-immunoprecipitation, co-IP with translation factors, siRNA knockdown, phosphorylation assays, polysome profiling Cell death & disease Medium 24113185
2015 Crystal structures of human TRAP1 complexed with Hsp90 inhibitors (including PU-H71) were determined, revealing the structural basis for inhibitor binding. Comparative structural analysis of a TRAP1–AMP-PNP complex proposed a molecular mechanism of ATP hydrolysis. Based on these structures, a mitochondria-targeted inhibitor (SMTIN-P01) was developed by replacing PU-H71's isopropyl amine with triphenylphosphonium. X-ray crystallography, structure-guided drug design, cell viability assays Journal of the American Chemical Society High 25785725
2017 In neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1 in the mitochondrial matrix. ERK1/2 enhances formation of this multimeric complex and SDH inhibition by TRAP1. ERK1/2 kinase activity is favored by interaction with TRAP1, and TRAP1 is phosphorylated in an ERK1/2-dependent manner. Mutagenesis of the ERK1/2-targeted serine residues on TRAP1 abrogates tumorigenicity. Co-immunoprecipitation, mitochondrial fractionation, phosphorylation assays, site-directed mutagenesis, SDH activity assay, tumor growth assay Cell reports High 28099845
2017 TRAP1 interacts with HTRA2 (identified by unbiased mass spectrometry). HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct proteolytic substrate of HTRA2. TRAP1 overexpression rescues HTRA2- and PINK1-associated mitochondrial dysfunction, indicating TRAP1 acts downstream of both HTRA2 and PINK1. A TRAP1 loss-of-function mutation in a Parkinson's disease patient results in increased oxygen consumption, ATP output, ROS, free NADH, mitochondrial biogenesis, and loss of mitochondrial membrane potential. Mass spectrometry interactome, co-immunoprecipitation, overexpression rescue, patient-derived fibroblast analysis, mitochondrial function assays Brain : a journal of neurology Medium 29050400
2014 TRAP1 silencing in TRAP1-null mice results in global upregulation of OXPHOS and glycolysis transcriptomes, causing deregulated mitochondrial respiration, oxidative stress, impaired cell proliferation, and a switch to glycolytic metabolism in vivo. TRAP1-null mice are viable but show reduced incidence of age-associated pathologies including obesity, inflammation, dysplasia, and spontaneous tumor formation. TRAP1 knockout mouse model, transcriptome profiling, bioenergetics analysis, in vivo metabolic phenotyping Cell reports High 25088416
2012 TRAP1 controls mitochondrial fusion/fission balance by regulating the expression of fission proteins Drp1 and Mff. Stable or transient TRAP1 knockdown reduces Drp1 and Mff protein levels (rescued by proteasome inhibitor MG132), without affecting fusion proteins, resulting in abnormal mitochondrial morphology. Stable and transient siRNA knockdown, proteasome inhibitor rescue, Western blot, mitochondrial morphology imaging PloS one Medium 23284813
2014 TRAP1 regulates BRAF synthesis/ubiquitination without affecting BRAF stability; BRAF synthesis is facilitated in a TRAP1-rich background while TRAP1 interference increases BRAF ubiquitination and decreases BRAF protein levels. TRAP1 silencing induces ERK phosphorylation attenuation, cell-cycle inhibition (accumulation at G0-G1 and G2-M), and extensive gene expression reprogramming. BRAF and TRAP1 are frequently co-expressed in human colorectal carcinomas. siRNA knockdown, overexpression, ubiquitination assay, Western blot, flow cytometry cell cycle analysis, gene expression profiling, IHC in tumor specimens Cancer research Medium 25239454
2017 TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with proteasome regulatory particle TBP7. This quality control of CDK1 is the limiting factor for TRAP1 regulation of the G2-M transition. TRAP1 silencing results in enhanced CDK1 ubiquitination, lack of nuclear translocation of CDK1/cyclin B1 complex, and increased MAD2 degradation. Forced CDK1 upregulation partially rescues the low cyclin B1, MAD2, and G2-M transit in TRAP1-poor cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, CDK1 overexpression rescue, flow cytometry, Western blot, gene expression profiling The Journal of pathology Medium 28678347
2020 TRAP1 forms a stable tetramer whose levels change in response to both increases and decreases in OXPHOS. TRAP1 ATPase activity is dispensable for restoring wild-type OXPHOS levels but modulates TRAP1 interactions with various mitochondrial proteins. The major quantitative TRAP1 interactors are mtHSP70 and HSP60. Disruption of TRAP1 dysregulates OXPHOS via metabolic rewiring that induces anaplerotic utilization of glutamine to replenish TCA cycle intermediates. TRAP1 knockout cell panel, native gel electrophoresis, quantitative mass spectrometry interactome, Seahorse respirometry, ATPase-dead mutant analysis, metabolomics BMC biology High 31987035
2020 Allosteric inhibitors of TRAP1 were identified using a dynamics-based computational approach targeting a pocket distal to the ATP-binding site. These inhibitors selectively inhibit TRAP1 but not Hsp90 ATPase activity and revert TRAP1-dependent downregulation of succinate dehydrogenase (SDH) activity in cancer cells and zebrafish larvae. Computational dynamics-based allosteric pocket identification, ATPase inhibition assay, SDH activity assay, cell proliferation assays, zebrafish model Cell reports High 32320652
2020 TRAP1 enhances Warburg metabolism through interaction with and regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); TRAP1–PFK1 interaction favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. This TRAP1–PFK1 interaction is lost under conditions of enhanced OXPHOS. Co-immunoprecipitation, ubiquitination assay, metabolic flux analysis (glucose uptake, lactate production, OXPHOS), patient-derived CRC spheroids Molecular oncology Medium 33025742
2020 S-nitrosylation of TRAP1 at Cys501 decreases TRAP1 ATPase activity as confirmed by colorimetric assays with recombinant TRAP1 and site-directed mutagenesis of C501S. The C501S mutant is more active and confers greater protection against staurosporine-induced cell death. Molecular dynamics simulations indicate Cys501 S-nitrosylation induces conformational changes to distal sites and alters open/closing motions of the chaperone. Site-directed mutagenesis (C501S), in vitro ATPase assay with recombinant protein, molecular dynamics simulation, cell death assay Biochemical pharmacology High 32088262
2021 Mitoquinone (MitoQ) inhibits TRAP1 by binding to previously unrecognized drug binding sites located in the middle domain of TRAP1 (the client binding region), as revealed by structural analyses. MitoQ competes with TRAP1 clients and its treatment enabled identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. Structural analysis (crystallography implied), client competition assay, mass spectrometry interactome, cell viability assays, in vivo tumor models Journal of the American Chemical Society High 34758612
2022 TRAP1 interacts with F-ATP synthase (at the OSCP subunit), competes with cyclophilin D (CyPD) for OSCP binding, increases F-ATP synthase catalytic activity, and directly inhibits the permeability transition pore (PTP) channel activity of purified F-ATP synthase in electrophysiological measurements. TRAP1 reverses CyPD-induced PTP opening and antagonizes CyPD-dependent mitochondrial depolarization and cell death. Co-immunoprecipitation, competition binding assay, ATPase activity assay, electrophysiology of purified F-ATP synthase, mitochondrial membrane potential assay, cell death assay Cell death and differentiation High 35614131
2022 Inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration under basal conditions but allows sustained OXPHOS when glucose is limiting. Under glucose limitation, the direct TRAP1–UQCRC2 interaction is disrupted while the broader TRAP1–complex III interaction is maintained. Co-immunoprecipitation, complex III activity assay, Seahorse respirometry, glucose deprivation experiments Cancer cell international Medium 36510251
2018 Calcium can replace magnesium as the enzymatic cofactor to support TRAP1 ATPase activity. Anomalous X-ray diffraction identified a calcium-binding site within the TRAP1 nucleotide-binding pocket, located near the ATP α-phosphate and distinct from the Mg²⁺-binding site. Calcium binding results in cooperative ATP hydrolysis by the two TRAP1 protomers within the dimer (vs. noncooperative hydrolysis with Mg²⁺). Anomalous X-ray diffraction crystallography, in vitro ATPase assay with defined divalent cations, cooperative kinetics analysis The Journal of biological chemistry High 29991590
2015 TRAP1 inhibits cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) opening in neural stem cells, preventing cytochrome c release and caspase-3 activation. Overexpression of Hsp75/TRAP1 preserved mitochondrial membrane potential and decreased NSC apoptosis induced by microglia-derived soluble factors. Overexpression, mPTP opening assay, mitochondrial membrane potential measurement, cytochrome c release assay, caspase-3 activation International journal of molecular medicine Medium 26500047
2014 In Drosophila, TRAP1 mutation activates a FOXO-dependent retrograde protective signal from mitochondria to the nucleus. TRAP1 mutation or knockdown markedly enhanced survival under oxidative stress and ameliorated mitochondrial dysfunction and DA neuron loss in PINK1 null mutants. Deletion of FOXO nullified the protective roles of TRAP1 mutation, establishing FOXO as a required downstream effector. Drosophila genetics (TRAP1 mutants, FOXO deletion), oxidative stress survival assays, DA neuron counting, mitochondrial function assays, Thor (FOXO target) expression measurement The Journal of biological chemistry Medium 26631731
2016 TRAP1 maintains cancer stem cell stemness in colorectal carcinoma through regulation of Wnt/β-catenin signaling. TRAP1 knockdown reduces stem cell marker expression and impairs colony formation. Mechanistically, TRAP1 modulates expression of frizzled receptor ligands and controls β-catenin ubiquitination/phosphorylation. siRNA knockdown, colony formation assay, Western blot (β-catenin ubiquitination/phosphorylation), gene expression profiling, IHC in human tumors Cell death and differentiation Medium 27662365
2021 HIF1α transcriptionally induces TRAP1 expression via conserved hypoxic responsive elements in the TRAP1 promoter. TRAP1 inhibition or genetic knockout maintains high mitochondrial respiration in zebrafish embryos exposed to hypoxia, identifying TRAP1 as a primary downstream effector of HIF1α in suppressing OXPHOS under oxygen limitation. Promoter analysis (HIF1α binding sites), HIF1α stabilization experiments, TRAP1 genetic knockout, zebrafish embryo respirometry, pharmacological inhibition Cell death & disease Medium 33934112
2014 TRAP1 activates the mitochondrial unfolded protein response (UPRmt) in Drosophila, promoting nuclear translocation of the homeobox protein Dve and increasing expression of UPRmt-associated genes. Genetic knockdown of UPRmt pathway components dampens the enhanced stress resistance observed with TRAP1 overexpression. Drosophila overexpression/knockdown, nuclear translocation imaging, UPRmt gene expression assays, genetic epistasis with UPRmt components Mechanisms of ageing and development Medium 25265088
2011 TRAP1 knockdown activates ER-resident caspase-4 (an ER stress-activated caspase) and increases basal BiP/Grp78 expression while decreasing basal CHOP expression, indicating TRAP1 modulates the unfolded protein response (UPR) in the ER. TRAP1 knockdown failed to activate caspase-9 in this context. siRNA knockdown, caspase-4 and caspase-9 activity assays, BiP/Grp78 and CHOP Western blot Neurochemistry international Medium 21338643
2019 c-Myc and N-Myc transcriptionally control TRAP1 expression in cancer cells (confirmed by ChIP assays). Myc-mediated TRAP1 induction preserves folding and function of mitochondrial OXPHOS complex II and IV subunits, dampens ROS, and enables oxidative bioenergetics. Genetic or pharmacological targeting of this Myc-TRAP1 pathway shuts off tumor cell motility, invasion, and suppresses primary and metastatic tumor growth in vivo. ChIP assay, siRNA knockdown, overexpression, metabolomics, bioenergetics, cell motility/invasion assays, in vivo tumor models The Journal of biological chemistry Medium 31097545
2024 TRAP1 promotes aerobic glycolysis, leading to elevated lactate production. Accumulated lactate down-regulates HDAC3 (histone lysine delactylase), increasing histone H4 lysine 12 lactylation (H4K12la) at SASP gene promoters, activating SASP transcription and exacerbating VSMC senescence. VSMC-specific TRAP1 knockout reduces plaque area, senescence markers, H4K12la, and SASP in atherosclerotic mice. VSMC-specific Trap1 knockout mice (ApoeKO background), ChIP analysis, lactylation assays, senescence markers (SA-β-gal), HDAC3 activity measurement European heart journal High 39088352

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS biology 498 17579517
2000 The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. The Journal of biological chemistry 294 10652318
2013 Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Proceedings of the National Academy of Sciences of the United States of America 225 23564345
2007 Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis. The Journal of biological chemistry 167 17513296
2011 TRAP-1, the mitochondrial Hsp90. Biochimica et biophysica acta 146 21878357
2007 Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress (Amsterdam, Netherlands) 144 17853063
2008 Overexpression of mitochondrial Hsp70/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 140 18985056
2024 TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. European heart journal 136 39088352
2009 TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells. Cancer letters 123 19217207
2010 Mitochondrial chaperone Trap1 and the calcium binding protein Sorcin interact and protect cells against apoptosis induced by antiblastic agents. Cancer research 118 20647321
2004 Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin. The Journal of biological chemistry 114 15292218
2012 The mitochondrial chaperone protein TRAP1 mitigates α-Synuclein toxicity. PLoS genetics 112 22319455
2015 Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1. Journal of the American Chemical Society 111 25785725
2017 The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells. Frontiers in oncology 109 28405578
2013 Drosophila Trap1 protects against mitochondrial dysfunction in a PINK1/parkin model of Parkinson's disease. Cell death & disease 107 23328674
2009 Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. The American journal of pathology 104 19948822
2007 Overexpression of mitochondrial Hsp70/Hsp75 protects astrocytes against ischemic injury in vitro. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 101 18091755
2013 Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney international 99 24152966
2011 TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins. Cell death and differentiation 86 21979464
2017 Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. Cell reports 82 28099845
2017 Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease. Brain : a journal of neurology 79 29050400
2013 TRAP1 rescues PINK1 loss-of-function phenotypes. Human molecular genetics 79 23525905
2000 Immunoelectron microscopy provides evidence that tumor necrosis factor receptor-associated protein 1 (TRAP-1) is a mitochondrial protein which also localizes at specific extramitochondrial sites. Experimental cell research 79 11010808
2018 TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor. Genes 78 29621137
2009 Heat shock proteins, cell survival and drug resistance: the mitochondrial chaperone TRAP1, a potential novel target for ovarian cancer therapy. Gynecologic oncology 75 19942270
2013 Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Molecular oncology 69 23735188
2020 Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1. Cell reports 65 32320652
2020 The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis. BMC biology 64 31987035
2013 Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1. Cell death & disease 64 24113185
2012 TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors. BMB reports 64 22281005
2007 Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor-associated protein 1 (TRAP1) regulates production of reactive oxygen species. Journal of cellular biochemistry 59 16927372
2014 Deletion of the mitochondrial chaperone TRAP-1 uncovers global reprogramming of metabolic networks. Cell reports 58 25088416
2012 New insights into TRAP1 pathway. American journal of cancer research 55 22432061
2016 TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma. Cell death and differentiation 54 27662365
2015 Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer. Oncotarget 53 26517089
2015 TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 51 26202366
2014 TRAP1 revisited: novel localizations and functions of a 'next-generation' biomarker (review). International journal of oncology 49 24990602
2011 Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum. Neurochemistry international 49 21338643
2010 Tumor necrosis factor receptor-associated protein 1(TRAP1) regulates genes involved in cell cycle and metastases. Cancer letters 46 20471161
2016 TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition. Cell death & disease 39 27977010
2014 TRAP1 is involved in BRAF regulation and downstream attenuation of ERK phosphorylation and cell-cycle progression: a novel target for BRAF-mutated colorectal tumors. Cancer research 39 25239454
2012 Role of TRAP1 and estrogen receptor alpha in patients with ovarian cancer -a study of the OVCAD consortium. Molecular cancer 38 22978347
2012 Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer. World journal of gastroenterology 38 23139614
2017 TRAP1 controls cell cycle G2-M transition through the regulation of CDK1 and MAD2 expression/ubiquitination. The Journal of pathology 37 28678347
2021 TRAP1 in Oxidative Stress and Neurodegeneration. Antioxidants (Basel, Switzerland) 36 34829705
2014 Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila. Mechanisms of ageing and development 36 25265088
2022 The mitochondrial chaperone TRAP1 regulates F-ATP synthase channel formation. Cell death and differentiation 35 35614131
2020 TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas. Molecular oncology 35 33025742
2017 Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1 in Oxidative Metabolism-Driven Inflammation. Advances in protein chemistry and structural biology 35 28427560
2012 TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression. PloS one 35 23284813
2021 Central role of TRAP1 in the ameliorative effect of oleanolic acid on the mitochondrial-mediated and endoplasmic reticulum stress-excitated apoptosis induced by ochratoxin A. Toxicology 34 33465424
2021 The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy. Frontiers in oncology 34 33575209
2017 Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity. Scientific reports 34 28397817
2015 Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1) Mutation and TRAP1 Inhibitor Gamitrinib-triphenylphosphonium (G-TPP) Induce a Forkhead Box O (FOXO)-dependent Cell Protective Signal from Mitochondria. The Journal of biological chemistry 34 26631731
2010 The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology 32 20961651
2022 TRAP1 Chaperones the Metabolic Switch in Cancer. Biomolecules 31 35740911
2017 TRAP1: a viable therapeutic target for future cancer treatments? Expert opinion on therapeutic targets 31 28664757
2015 Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: a novel strategy for human BRAF-driven colorectal carcinoma. Oncotarget 31 26084290
2014 TRAP1 shows clinical significance and promotes cellular migration and invasion through STAT3/MMP2 pathway in human esophageal squamous cell cancer. Journal of genetics and genomics = Yi chuan xue bao 31 25438697
2021 Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives. Trends in pharmacological sciences 30 33992469
2020 Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1. Antioxidants & redox signaling 30 32438819
2020 Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems. Cells 29 32664214
2016 Transgenic Expression of the Mitochondrial Chaperone TNFR-associated Protein 1 (TRAP1) Accelerates Prostate Cancer Development. The Journal of biological chemistry 29 27754870
2014 TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: relevance in human colorectal tumors. Molecular oncology 29 24962791
2016 Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells. Cell stress & chaperones 28 27072803
2021 HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia. Cell death & disease 27 33934112
2021 Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site. Journal of the American Chemical Society 27 34758612
2019 Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth. The Journal of biological chemistry 27 31097545
2019 Ameliorative effect of ursolic acid on ochratoxin A-induced renal cytotoxicity mediated by Lonp1/Aco2/Hsp75. Toxicon : official journal of the International Society on Toxinology 27 31356822
2017 Clinicopathologic significance of TRAP1 expression in colorectal cancer: a large scale study of human colorectal adenocarcinoma tissues. Diagnostic pathology 27 28088229
2014 Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer. World journal of gastroenterology 27 25493016
2013 TRAP1 role in endoplasmic reticulum stress protection favors resistance to anthracyclins in breast carcinoma cells. International journal of oncology 27 24297638
2020 Mitochondrial chaperone, TRAP1 modulates mitochondrial dynamics and promotes tumor metastasis. Mitochondrion 26 32784002
2008 Mitochondrial DNA variability modulates mRNA and intra-mitochondrial protein levels of HSP60 and HSP75: experimental evidence from cybrid lines. Cell stress & chaperones 26 18815895
2020 S-nitrosylation affects TRAP1 structure and ATPase activity and modulates cell response to apoptotic stimuli. Biochemical pharmacology 25 32088262
2014 The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET. Cellular logistics 25 25750764
2010 Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy. Cancer immunology, immunotherapy : CII 25 20499060
2016 TRAP1 regulates cell cycle and apoptosis in thyroid carcinoma cells. Endocrine-related cancer 24 27422900
2014 Overexpression of tumor necrosis factor receptor-associated protein 1 (TRAP1), leads to mitochondrial aberrations in mouse fibroblast NIH/3T3 cells. BMB reports 23 24286320
2017 TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma. Oncotarget 22 28177905
2017 TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 28710113
2011 HSP75 protects against cardiac hypertrophy and fibrosis. Journal of cellular biochemistry 22 21381076
2011 Concomitant inhibition of HSP90, its mitochondrial localized homologue TRAP1 and HSP27 by green tea in pancreatic cancer HPAF-II cells. Proteomics 22 22116673
1997 Identification and characterization of a constitutive HSP75 in sea urchin embryos. Biochemical and biophysical research communications 22 9168953
2019 Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors. Cancers 21 31181660
2015 TRAP1 controls cell migration of cancer cells in metabolic stress conditions: Correlations with AKT/p70S6K pathways. Biochimica et biophysica acta 21 26071104
2015 Overexpression of mitochondrial Hsp75 protects neural stem cells against microglia-derived soluble factor-induced neurotoxicity by regulating mitochondrial permeability transition pore opening in vitro. International journal of molecular medicine 21 26500047
2014 Combination of TRAP1 and ERCC1 Expression Predicts Clinical Outcomes in Metastatic Colorectal Cancer Treated with Oxaliplatin/5-Fluorouracil. Cancer research and treatment 21 24520224
2004 Translocation of the Dictyostelium TRAP1 homologue to mitochondria induces a novel prestarvation response. Journal of cell science 21 15507488
2002 Unique behavior of a dictyostelium homologue of TRAP-1, coupling with differentiation of D. discoideum cells. Experimental cell research 21 12372338
2022 Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1. Journal of medicinal chemistry 20 36507721
2015 Functional characterization of TRAP1-like protein involved in modulating fibrotic processes mediated by TGF-β/Smad signaling in hypertrophic scar fibroblasts. Experimental cell research 20 25655281
2005 Changes in spatial and temporal localization of Dictyostelium homologues of TRAP1 and GRP94 revealed by immunoelectron microscopy. Experimental cell research 20 15652353
2023 Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 37983591
2021 TRAP1 suppresses oral squamous cell carcinoma progression by reducing oxidative phosphorylation metabolism of Cancer-associated fibroblasts. BMC cancer 19 34906113
2022 Regulation of mitochondrial complex III activity and assembly by TRAP1 in cancer cells. Cancer cell international 18 36510251
2018 Calcium binding to a remote site can replace magnesium as cofactor for mitochondrial Hsp90 (TRAP1) ATPase activity. The Journal of biological chemistry 18 29991590
2017 Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model. Oncotarget 18 28407697
2016 Downregulation of TRAP1 sensitizes glioblastoma cells to temozolomide chemotherapy through regulating metabolic reprogramming. Neuroreport 18 26716385
2012 Heat shock protein genes (hsp20, hsp75 and hsp90) from Pieris rapae: molecular cloning and transcription in response to parasitization by Pteromalus puparum. Insect science 18 23955859

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