Affinage

TRAP1

Heat shock protein 75 kDa, mitochondrial · UniProt Q12931

Length
704 aa
Mass
80.1 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAP1 is a mitochondrial matrix-localized HSP90-family chaperone that functions as a central regulator of mitochondrial bioenergetics, quality control, and cell survival. Its intrinsic ATPase activity, driven by an N-terminal strap-regulated conformational cycle distinct from cytosolic Hsp90, is modulated by PINK1-dependent phosphorylation, ERK1/2-dependent phosphorylation at SDH-regulatory sites, and Cys501 S-nitrosylation (PMID:10652318, PMID:25531069, PMID:17579517, PMID:28099845, PMID:32088262). TRAP1 inhibits succinate dehydrogenase (complex II) and directly binds the OSCP subunit of F-ATP synthase to antagonize cyclophilin D and suppress permeability transition pore opening, while also interacting with PFK1 and c-Src to control the balance between oxidative phosphorylation and glycolysis — a metabolic output that drives lactate-dependent histone H4K12 lactylation and senescence-associated gene expression in vascular cells (PMID:28099845, PMID:35614131, PMID:23564345, PMID:33025742, PMID:39088352). Beyond mitochondria, TRAP1 localizes to the ER where it partners with the 19S proteasomal subunit TBP7 to regulate ubiquitination of mitochondria-destined proteins, and it modulates translation through the eIF2α/GCN2/PERK integrated stress response pathway (PMID:21979464, PMID:24113185).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Establishing TRAP1 as a mitochondrial matrix ATPase distinct from cytosolic Hsp90 resolved its subcellular identity and enzymatic classification, showing it binds ATP and is geldanamycin-sensitive but lacks canonical Hsp90 co-chaperone interactions.

    Evidence Immunofluorescence, subcellular fractionation, in vitro ATPase assay, co-chaperone binding assays in human cells; quantitative immunogold EM across tissues

    PMID:10652318 PMID:11010808

    Open questions at the time
    • Endogenous mitochondrial substrates/clients unknown
    • Functional significance of extramitochondrial pools unresolved
  2. 2007 High

    Demonstrating that PINK1 phosphorylates TRAP1 in mitochondria to suppress cytochrome c release linked TRAP1 directly to the Parkinson's disease PINK1-parkin pathway and established its cytoprotective role against oxidative stress.

    Evidence Co-IP, in vitro kinase assay, cytochrome c release assay, PD-mutant PINK1 epistasis in mammalian cells; granzyme M cleavage of TRAP1 with ROS/apoptosis readouts

    PMID:17513296 PMID:17579517

    Open questions at the time
    • TRAP1 phosphorylation site(s) by PINK1 not mapped
    • Relationship to parkin-dependent mitophagy unclear
  3. 2008 High

    Quantitative kinetic dissection of TRAP1's full ATPase cycle revealed that hydrolysis (not lid closure) is rate-limiting, providing the mechanistic framework for understanding how post-translational modifications and inhibitors regulate chaperone function.

    Evidence Stopped-flow rapid kinetics, global fitting of ATPase cycle with purified recombinant TRAP1

    PMID:18287101

    Open questions at the time
    • How client binding alters the kinetic cycle unknown
    • Physiological temperature regulation not yet explained
  4. 2011 High

    Discovery of TRAP1 at the ER in complex with TBP7/Rpt3, controlling ubiquitination of mitochondria-destined proteins, expanded TRAP1 function beyond the mitochondrial matrix to organelle quality control at the ER-mitochondria interface.

    Evidence FRET-confirmed direct interaction, electron microscopy co-localization, ubiquitination and ER stress assays with shRNA silencing

    PMID:21979464

    Open questions at the time
    • Identity of specific TBP7-TRAP1 client proteins not fully defined
    • Mechanism of TRAP1 ER targeting not established
  5. 2013 High

    Multiple groups demonstrated that TRAP1 deficiency increases OXPHOS and that TRAP1 interacts with mitochondrial c-Src, establishing TRAP1 as a metabolic switch between oxidative phosphorylation and glycolysis — a fundamental reframing from chaperone to metabolic regulator.

    Evidence TRAP1-null cells, Seahorse metabolic flux, metabolomics, Co-IP with c-Src; parallel Drosophila genetic epistasis placing Trap1 downstream of Pink1

    PMID:23328674 PMID:23525905 PMID:23564345

    Open questions at the time
    • Direct mechanism by which TRAP1 inhibits OXPHOS complexes not yet identified at molecular level
    • Relative contributions of c-Src-dependent versus independent pathways unclear
  6. 2013 Medium

    Showing that TRAP1 associates with ribosomes and activates GCN2/PERK-eIF2α signaling to attenuate cap-dependent translation revealed an unexpected role in translational control of stress-responsive genes.

    Evidence Co-IP with ribosomes/translation factors, polysome profiling, eIF2α phosphorylation with TRAP1 silencing/overexpression in colon carcinoma cells

    PMID:24113185

    Open questions at the time
    • Direct versus indirect ribosome association not distinguished
    • Not independently replicated
    • Whether translational control is mitochondria-dependent unclear
  7. 2014 High

    Crystal structures revealed that TRAP1's unique N-terminal strap stabilizes the closed conformation via trans-protomer contacts and imposes a thermal kinetic barrier, explaining its temperature-dependent ATPase behavior and providing the first atomic-level model of TRAP1 regulation.

    Evidence X-ray crystallography of TRAP1, strap mutagenesis, temperature-dependent ATPase assays

    PMID:25531069 PMID:25785725

    Open questions at the time
    • No client-bound TRAP1 structure available
    • In vivo relevance of temperature-sensing unclear
  8. 2016 High

    Identification of Cys501 as the S-nitrosylation site that triggers TRAP1 proteasomal degradation and consequent SDH derepression provided the first evidence that TRAP1 directly restrains SDH activity and that redox modification controls TRAP1 turnover.

    Evidence C501 mutagenesis, S-nitrosylation detection, proteasome inhibitor rescue, SDH activity assay in GSNOR-deficient cells

    PMID:27216192

    Open questions at the time
    • Whether Cys501 modification occurs under physiological conditions in vivo not shown
    • Structural basis for SNO-induced degradation unknown
  9. 2017 High

    Demonstrating that mitochondrial ERK1/2 phosphorylates TRAP1 to enhance TRAP1-SDH complex formation and SDH inhibition in neurofibromin-deficient tumors established a direct kinase-chaperone-metabolic enzyme signaling axis linking RAS-ERK signaling to succinate accumulation.

    Evidence ERK kinase assay on TRAP1, site-directed serine mutagenesis, SDH activity, Co-IP, tumorigenicity assays

    PMID:28099845

    Open questions at the time
    • Precise TRAP1 serine residues phosphorylated by ERK not all mapped
    • Whether other oncogenic kinases similarly regulate TRAP1-SDH unknown
  10. 2017 High

    Identification of TRAP1-HTRA2 interaction and characterization of a PD patient TRAP1 loss-of-function mutation showing increased OXPHOS and ROS provided human genetic evidence linking TRAP1 dysfunction to Parkinson's disease-related mitochondrial phenotypes.

    Evidence MS-based interactomics, overexpression epistasis of TRAP1 with HTRA2/PINK1, metabolic profiling of patient-derived fibroblasts

    PMID:29050400

    Open questions at the time
    • Single patient — genetic causality not formally proven
    • Whether HTRA2 regulates TRAP1 levels directly or indirectly unresolved
  11. 2020 High

    Discovery that TRAP1 forms a stable mitochondrial tetramer whose ATPase activity is dispensable for OXPHOS regulation but modulates client interactions fundamentally revised the assumption that ATP hydrolysis directly mediates TRAP1's metabolic function.

    Evidence Native gel, size exclusion chromatography, quantitative MS interactomics, ATPase-dead mutant reconstitution in TRAP1-KO cells

    PMID:31987035

    Open questions at the time
    • Tetramer architecture and stoichiometry not structurally resolved
    • Whether tetramer is the functional unit for all TRAP1 activities unknown
  12. 2020 Medium

    Showing that TRAP1 stabilizes PFK1 by preventing its ubiquitination directly connected TRAP1's chaperone activity to glycolytic flux regulation, complementing its OXPHOS-suppressive role via SDH inhibition.

    Evidence Co-IP of TRAP1-PFK1, PFK1 ubiquitination and activity assays, metabolic flux measurements with siRNA knockdown

    PMID:33025742

    Open questions at the time
    • Direct binding domain on PFK1 not mapped
    • Not independently replicated
  13. 2021 High

    Structural identification of MitoQ binding to an asymmetric bipartite site in TRAP1's middle (client-binding) domain enabled mapping of 103 TRAP1-interacting mitochondrial proteins and revealed a novel drug-targetable region distinct from the ATP pocket.

    Evidence Structural analysis of TRAP1-MitoQ complex, client competition assay, AP-MS interactome in cancer cells

    PMID:34758612

    Open questions at the time
    • Selectivity of middle-domain binders for TRAP1 over Hsp90 in vivo not fully established
    • Client hierarchy and essentiality among 103 interactors unknown
  14. 2022 High

    Demonstrating that TRAP1 directly binds the OSCP subunit of F-ATP synthase and competitively displaces cyclophilin D to inhibit permeability transition pore opening provided the first defined molecular mechanism for TRAP1's long-known anti-apoptotic function at the inner mitochondrial membrane.

    Evidence Co-IP, competitive CyPD displacement, electrophysiology of purified F-ATP synthase PTP channel, mitochondrial membrane potential and cell death assays

    PMID:35614131

    Open questions at the time
    • Whether TRAP1's ATPase cycle is required for OSCP binding unknown
    • Structural basis of TRAP1-OSCP interface not resolved
  15. 2024 High

    An in vivo mouse study showed that TRAP1-driven glycolysis and lactate production leads to HDAC3 downregulation and H4K12 lactylation at SASP gene promoters, establishing a mitochondrial chaperone → metabolite → epigenetic axis that drives vascular smooth muscle cell senescence and atherosclerosis.

    Evidence VSMC-specific Trap1 knockout mice, ChIP for H4K12la at SASP promoters, lactate measurements, atherosclerosis model

    PMID:39088352

    Open questions at the time
    • Whether this lactylation axis operates in non-vascular tissues unknown
    • Direct mechanism by which TRAP1 upregulates glycolysis in VSMCs not distinguished from SDH/PFK1 pathways

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TRAP1-client recognition within the tetramer, the precise mechanism by which TRAP1 inhibits SDH (direct binding mode versus allosteric effect), the physiological relevance of TRAP1's temperature-sensing strap in warm-blooded organisms, and whether TRAP1 mutations are causative for Parkinson's disease beyond a single case report.
  • No client-bound TRAP1 tetramer structure
  • SDH inhibition mechanism at atomic resolution unresolved
  • TRAP1 mutations not yet validated as PD-causative in cohort studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 6 GO:0044183 protein folding chaperone 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005739 mitochondrion 9 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ATP5POHSPA9HTRA2PFKMPINK1SDHASRCSRI
Complex memberships
TRAP1 tetramerTRAP1-F-ATP synthase (OSCP) complexTRAP1-SDH complexTRAP1-TBP7 (ER quality control complex)

Evidence

Reading pass · 31 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, binds ATP, and exhibits ATPase activity inhibitable by geldanamycin and radicicol; however, unlike Hsp90, it does not form stable complexes with co-chaperones p23 or Hop and cannot substitute for Hsp90 in progesterone receptor reconstitution. Immunofluorescence, subcellular fractionation, in vitro ATPase assay, co-chaperone binding assays, hormone-binding reconstitution assay The Journal of biological chemistry High 10652318
2000 TRAP1 is primarily a mitochondrial matrix protein, but is also detected at specific extramitochondrial sites including pancreatic zymogen granules, insulin secretory granules, cardiac sarcomeres, nuclei, and endothelial cell surfaces by immunogold electron microscopy. Quantitative immunogold electron microscopy, Western blot of purified subcellular fractions, immunofluorescence Experimental cell research High 11010808
2007 PINK1 kinase binds TRAP1 in mitochondria and phosphorylates TRAP1 both in vitro and in vivo; this phosphorylation is required for PINK1-mediated suppression of cytochrome c release and protection against oxidative-stress-induced apoptosis. PD-linked PINK1 mutations (G309D, L347P, W437X) impair TRAP1 phosphorylation and cell survival. Co-immunoprecipitation, in vitro kinase assay, colocalization by immunofluorescence, cytochrome c release assay, cell death assay with kinase-dead and PD-mutant PINK1 PLoS biology High 17579517
2007 Granzyme M cleaves TRAP1, abolishing its antioxidant function, leading to ROS accumulation, cytochrome c release, and apoptosis. TRAP1 overexpression attenuates ROS production whereas TRAP1 silencing increases ROS accumulation. In vitro cleavage assay, RNAi knockdown, overexpression, ROS measurement, cytochrome c release assay The Journal of biological chemistry High 17513296
2008 TRAP1 (Trap1) undergoes an ATP-dependent conformational cycle: ATP binding drives closure (rate ~0.076 s⁻¹), reopening is ~10× faster than hydrolysis (rate-limiting step kₕᵧd ~0.0039 s⁻¹), and ADP release follows. This ATPase cycle is distinct from cytosolic Hsp90. Biochemical ATPase assays, stopped-flow rapid kinetics, thermodynamic analysis, global fitting of kinetic model The Journal of biological chemistry High 18287101
2010 TRAP1 interacts with the Ca²⁺-binding protein Sorcin in mitochondria; this interaction is required for Sorcin mitochondrial localization and TRAP1 stability. TRAP1 depletion reduces mitochondrial Sorcin, while Sorcin depletion increases TRAP1 degradation, and both proteins cooperate in cytoprotection. Proteomic co-immunoprecipitation/mass spectrometry, fluorescence microscopy, Western blot of mitochondrial subfractions, reciprocal siRNA knockdown Cancer research High 20647321
2011 TRAP1 localizes to the endoplasmic reticulum (ER) where it interacts directly with TBP7 (Rpt3), a 19S proteasomal subunit; this complex controls ubiquitination and stability of specific nuclear-encoded mitochondrial proteins. TRAP1 silencing upregulates BiP/Grp78 under ER stress and enhances protein ubiquitination. Mass spectrometry, co-immunoprecipitation, confocal and electron microscopy, FRET analysis, shRNA silencing, ubiquitination assay, thapsigargin-induced ER stress Cell death and differentiation High 21979464
2013 TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis; TRAP1 deficiency increases mitochondrial respiration, fatty acid oxidation, TCA cycle intermediates, ATP, and ROS while suppressing glucose metabolism. TRAP1 interaction with mitochondrial c-Src provides a mechanistic basis for these metabolic phenotypes. TRAP1-null cells, siRNA silencing, overexpression, Seahorse metabolic flux analysis, metabolomics, co-immunoprecipitation with c-Src, invasion assay Proceedings of the National Academy of Sciences of the United States of America High 23564345
2013 TRAP1 is associated with ribosomes and translation factors in colon carcinoma cells and regulates the rate of protein synthesis through the eIF2α pathway by activating GCN2 and PERK kinases, leading to eIF2α phosphorylation, attenuation of cap-dependent translation, and selective synthesis of stress-responsive proteins (ATF4, BiP/Grp78, xCT). Co-immunoprecipitation with ribosomes/translation factors, polysome profiling, eIF2α phosphorylation assay, kinase activation assay, TRAP1 silencing/overexpression Cell death & disease Medium 24113185
2013 In Drosophila, Trap1 works downstream of Pink1 and in parallel with parkin; overexpression of Trap1 in neurons rescues mitochondrial impairment caused by Pink1 loss but not parkin loss, establishing genetic epistasis in the PINK1-parkin pathway. Drosophila genetic epistasis, Trap1 null mutants, neuronal overexpression rescue, mitochondrial function assays, oxidative stress assays Cell death & disease High 23328674
2013 TRAP1 overexpression rescues PINK1 loss-of-function phenotypes (mitochondrial fragmentation, dysfunction) in Drosophila and human SH-SY5Y cells, and rescues Complex I subunit RNAi phenotypes; TRAP1 does not rescue parkin loss-of-function, placing TRAP1 downstream of PINK1 and complex I but parallel to/upstream of Parkin. Drosophila in vivo genetics, siRNA silencing in human neuronal cells, mitochondrial morphology imaging, functional assays Human molecular genetics High 23525905
2014 The N-terminal 'strap' extension of TRAP1 stabilizes the closed (ATP-bound) conformation through trans-protomer interactions, creating a thermally sensitive kinetic barrier between the open and closed conformations. Strap displacement is coupled to N-terminal domain rotation and nucleotide binding pocket lid dynamics, explaining unusual temperature dependence of TRAP1 ATPase rates. Crystal structure of TRAP1, mutagenesis of the strap, ATPase assays at different temperatures, biochemical conformational analysis eLife High 25531069
2015 Crystal structures of human TRAP1 complexed with Hsp90 inhibitors revealed the ATP-binding mode; structural comparison led to development of SMTIN-P01 (mitochondria-targeted TRAP1 inhibitor). The structure of TRAP1-AMP-PNP complex provided a molecular mechanism for ATP hydrolysis central to chaperone function. X-ray crystallography of TRAP1-inhibitor and TRAP1-AMP-PNP complexes, structure-guided drug design, cellular cytotoxicity assays Journal of the American Chemical Society High 25785725
2016 TRAP1 is S-nitrosylated at Cys501, which mediates its proteasomal degradation. GSNOR deficiency causes selective S-nitrosylation of Cys501-TRAP1, leading to TRAP1 degradation and consequently elevated succinate dehydrogenase (SDH) levels and activity. Site-directed mutagenesis (C501), S-nitrosylation detection assays, proteasome inhibitor rescue, SDH activity assay in GSNOR-deficient cells Cancer research High 27216192
2017 In neurofibromin-deficient cells, a fraction of active ERK1/2 localizes to the mitochondrial matrix and associates with TRAP1 and succinate dehydrogenase (SDH); ERK1/2 phosphorylates TRAP1 and enhances TRAP1-SDH complex formation, increasing SDH inhibition and succinate accumulation. TRAP1 mutagenesis at ERK1/2-targeted serine residues abrogates tumorigenicity. Mitochondrial fractionation, co-immunoprecipitation, ERK kinase activity assay on TRAP1, site-directed mutagenesis of TRAP1 serine residues, SDH activity assay, tumorigenicity assay Cell reports High 28099845
2017 TRAP1 interacts with HTRA2 (identified by mass spectrometry); HTRA2 regulates TRAP1 protein levels (but TRAP1 is not a direct proteolytic target of HTRA2). TRAP1 acts downstream of both HTRA2 and PINK1 in mitochondrial fine-tuning; loss-of-function TRAP1 mutation in a PD patient leads to increased oxygen consumption, ATP output, ROS, free NADH, and mitochondrial biogenesis, with reduced membrane potential. Unbiased mass spectrometry interactomics, TRAP1 overexpression rescue of HTRA2/PINK1 dysfunction, patient-derived fibroblast metabolic analysis (Seahorse, ROS, membrane potential, mtDNA) Brain : a journal of neurology High 29050400
2017 TRAP1 silencing in colorectal carcinoma cells reduces BRAF protein levels by increasing BRAF ubiquitination without affecting mRNA stability; BRAF and TRAP1 interact directly; BRAF signaling induces TRAP1 serine phosphorylation, which correlates with apoptosis resistance. Co-immunoprecipitation (BRAF-TRAP1), ubiquitination assay, siRNA silencing, BRAF dominant-negative mutant, Western blot, cell death assay Cancer research Medium 25239454
2017 TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with TBP7; TRAP1 silencing enhances CDK1 and MAD2 ubiquitination, prevents nuclear translocation of the CDK1/cyclin B1 complex, and increases MAD2 degradation, blocking G2-M transition. Co-immunoprecipitation (TRAP1-CDK1), ubiquitination assay, siRNA knockdown, nuclear fractionation, flow cytometry cell cycle analysis, gene expression profiling The Journal of pathology Medium 28678347
2017 TRAP1 maintains stemness in colorectal cancer through modulation of Wnt/β-catenin signaling; TRAP1 knockdown reduces expression of frizzled receptor ligands, increases β-catenin ubiquitination/phosphorylation, and reduces β-catenin levels and Wnt target gene expression. siRNA knockdown, gene expression profiling, β-catenin ubiquitination and phosphorylation assays, colony formation, CSC sorting assays Cell death and differentiation Medium 27662365
2019 c-Myc and N-Myc transcriptionally control TRAP1 expression (shown by ChIP assays); Myc-driven TRAP1 expression preserves folding and function of mitochondrial OXPHOS complex II and IV subunits, dampens ROS, and enables oxidative bioenergetics in tumor cells. ChIP assays (Myc binding to TRAP1 promoter), siRNA silencing, metabolomics, bioenergetics assays, in vivo tumor models The Journal of biological chemistry High 31097545
2020 TRAP1 forms a stable stoichiometric tetramer in mitochondria whose levels respond to changes in OXPHOS; TRAP1 ATPase activity is dispensable for OXPHOS regulation but modulates interactions with mitochondrial proteins; major interactors are mtHSP70 and HSP60. Native gel electrophoresis, size exclusion chromatography, quantitative MS interactomics, TRAP1 knockout and reconstitution with ATPase mutants, metabolic flux analysis BMC biology High 31987035
2020 TRAP1 interacts with phosphofructokinase-1 (PFK1), preventing its ubiquitination/degradation and favoring its glycolytic activity; this interaction is lost under conditions of enhanced OXPHOS, providing a mechanistic basis for TRAP1-regulated glycolysis and lactate production. Co-immunoprecipitation (TRAP1-PFK1), ubiquitination assay, PFK1 activity assay, siRNA knockdown, metabolic flux measurements Molecular oncology Medium 33025742
2020 A computationally identified allosteric pocket distal to the TRAP1 active site can host drug-like molecules that selectively inhibit TRAP1 (but not Hsp90) ATPase activity and revert TRAP1-dependent downregulation of succinate dehydrogenase (SDH) activity in cancer cells. Molecular dynamics, in vitro ATPase assay with recombinant TRAP1, SDH activity assay in cells and zebrafish larvae, cell viability assays Cell reports High 32320652
2020 S-nitrosylation of TRAP1 at Cys501 decreases its ATPase activity and alters conformational dynamics at distal sites; the C501S mutant shows enhanced ATPase activity and greater protection against staurosporine-induced cell death. Site-directed mutagenesis (C501S), colorimetric ATPase assay, molecular dynamics simulation, cell death assay Biochemical pharmacology High 32088262
2021 HIF1α directly induces TRAP1 transcription via conserved hypoxic responsive elements in the TRAP1 promoter; TRAP1 acts downstream of HIF1α to dampen mitochondrial respiration under hypoxia in cancer cells and developing zebrafish embryos. Promoter analysis, HIF1α stabilization experiments, TRAP1 genetic knockout and pharmacological inhibition, Seahorse metabolic analysis in cells and zebrafish larvae Cell death & disease Medium 33934112
2022 TRAP1 directly binds the OSCP subunit of mitochondrial F-ATP synthase, competing with cyclophilin D (CyPD) for the same binding site; TRAP1 binding increases F-ATP synthase catalytic activity, counteracts CyPD inhibitory effect, and directly inhibits the permeability transition pore (PTP) channel activity of purified F-ATP synthase, reversing CyPD-mediated PTP induction. Co-immunoprecipitation (TRAP1-OSCP), competitive binding assay with CyPD, purified F-ATP synthase electrophysiology (patch clamp of PTP channel), mitochondrial membrane potential assay, cell death assay Cell death and differentiation High 35614131
2021 MitoQ (mitoquinone) binds an asymmetric bipartite site in the middle domain of TRAP1 (the client binding region), competes with TRAP1 clients, and enabled identification of 103 TRAP1-interacting mitochondrial proteins. Structural analysis revealed this middle-domain site as a novel drug binding region distinct from the ATP-binding site. Structural analysis of TRAP1-MitoQ complex, client competition assay, affinity purification-MS of TRAP1 interactome in cancer cells, cell viability assays in vitro and in vivo Journal of the American Chemical Society High 34758612
2024 TRAP1 promotes aerobic glycolysis and lactate production in vascular smooth muscle cells, leading to elevated lactate that downregulates HDAC3 and causes histone H4 lysine 12 lactylation (H4K12la) at SASP gene promoters, activating SASP transcription and driving VSMC senescence. VSMC-specific TRAP1 knockout reduces H4K12la, SASP, and atherosclerosis in mice. VSMC-specific Trap1 knockout mice, ChIP analysis for H4K12la at SASP promoters, metabolic measurement (lactate), Western blot, senescence assays, in vivo atherosclerosis model European heart journal High 39088352
2012 TRAP1 controls mitochondrial fusion/fission balance by regulating the expression of fission proteins Drp1 and Mff; TRAP1 knockdown reduces Drp1 and Mff protein levels (rescued by proteasome inhibitor MG132) without affecting fusion protein levels, leading to abnormal mitochondrial morphology. Stable and transient siRNA knockdown in multiple cell lines, Western blot, proteasome inhibitor rescue, mitochondrial morphology microscopy PloS one Medium 23284813
2011 TRAP1 knockdown activates ER-resident caspase-4 but increases basal BiP/Grp78 expression and decreases CHOP expression, indicating mitochondrial TRAP1 modulates the unfolded protein response (UPR) in the ER. siRNA knockdown, caspase-4 activation assay, BiP/Grp78 and CHOP Western blot, cell death assay under ER stress Neurochemistry international Low 21338643
2023 TRAP1 inhibition (genetic Trap1 ablation or MitoQ/SB-U015 treatment) causes mitochondrial permeability transition pore opening, activates the calcium-dependent protease calpain-1, and promotes proteolytic HIF1α degradation, thereby alleviating pathological retinal neovascularization. Trap1 knockout mouse models of ischemic retinopathy, pharmacological TRAP1 inhibitors, mPTP opening assay, calpain-1 activity assay, HIF1α degradation assay, retinal vascular pathology readouts Advanced science Medium 37983591

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 497 17579517
2000 The hsp90-related protein TRAP1 is a mitochondrial protein with distinct functional properties. The Journal of biological chemistry 293 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 224 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
2009 TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells. Cancer letters 122 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
2024 TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. European heart journal 113 39088352
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 103 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 100 18091755
2013 Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney international 99 24152966
2020 Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1. Experimental & molecular medicine 88 31956271
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 85 21979464
2017 Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. Cell reports 81 28099845
2013 TRAP1 rescues PINK1 loss-of-function phenotypes. Human molecular genetics 79 23525905
2008 The ATPase cycle of the mitochondrial Hsp90 analog Trap1. The Journal of biological chemistry 79 18287101
2017 Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease. Brain : a journal of neurology 78 29050400
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 78 11010808
2018 TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor. Genes 77 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
2016 S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase. Cancer research 65 27216192
2020 Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1. Cell reports 64 32320652
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
2020 The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis. BMC biology 63 31987035
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 53 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
2014 A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity. eLife 39 25531069
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
2022 The mitochondrial chaperone TRAP1 regulates F-ATP synthase channel formation. Cell death and differentiation 35 35614131
2021 TRAP1 in Oxidative Stress and Neurodegeneration. Antioxidants (Basel, Switzerland) 35 34829705
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
2014 Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila. Mechanisms of ageing and development 35 25265088
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
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
2010 The TGF-β signaling modulators TRAP1/TGFBRAP1 and VPS39/Vam6/TLP are essential for early embryonic development. Immunobiology 31 20961651
2021 Targeting the mitochondrial chaperone TRAP1: strategies and therapeutic perspectives. Trends in pharmacological sciences 30 33992469
2022 The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors. Biomolecules 29 35883436
2020 Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1. Antioxidants & redox signaling 29 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
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
2013 TRAP1 role in endoplasmic reticulum stress protection favors resistance to anthracyclins in breast carcinoma cells. International journal of oncology 27 24297638
2021 Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site. Journal of the American Chemical Society 26 34758612
2020 Mitochondrial chaperone, TRAP1 modulates mitochondrial dynamics and promotes tumor metastasis. Mitochondrion 26 32784002
2014 Up-regulation of mitochondrial chaperone TRAP1 in ulcerative colitis associated colorectal cancer. World journal of gastroenterology 26 25493016
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
2020 Machine Learning of Allosteric Effects: The Analysis of Ligand-Induced Dynamics to Predict Functional Effects in TRAP1. The journal of physical chemistry. B 24 33369425
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 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
2017 TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma. Oncotarget 21 28177905
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
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
2022 Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1. Journal of medicinal chemistry 19 36507721
2023 Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 37983591
2021 TRAP1 suppresses oral squamous cell carcinoma progression by reducing oxidative phosphorylation metabolism of Cancer-associated fibroblasts. BMC cancer 18 34906113
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