Affinage

HSPD1

60 kDa heat shock protein, mitochondrial · UniProt P10809

Round 2 corrected
Length
573 aa
Mass
61.1 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSPD1 encodes the mitochondrial 60 kDa chaperonin (HSP60), an ATP-dependent Group I chaperonin essential for folding proteins imported into the mitochondrial matrix and for maintaining mitochondrial proteostasis, with additional extra-mitochondrial roles in apoptosis regulation and innate immune signaling. HSP60 binds non-native polypeptides at hydrophobic apical-domain sites, undergoes ATP-driven conformational changes to encapsulate substrates with co-chaperonin HSPE1/HSP10 in a hydrophilic folding cavity, and promotes folding through chain-collapse enhancement and cavity confinement before releasing substrates upon ATP hydrolysis; unlike bacterial GroEL, mammalian HSP60 exists as single heptameric rings in the apo state and assembles into symmetric double-ring "football" complexes only upon ATP binding and HSP10 association (PMID:2528694, PMID:26427351, PMID:29295923, PMID:35245117). Outside the mitochondrial matrix, HSP60 forms complexes with survivin, p53, and Bax/Bak to regulate apoptosis in a compartment-dependent manner—stabilizing survivin and restraining p53 in mitochondria while promoting caspase-3 activation upon cytosolic release—and is secreted via exosomes to activate TLR4–MyD88–NF-κB inflammatory signaling (PMID:10205158, PMID:18086682, PMID:17307989, PMID:23447644). Loss-of-function mutations (D29G, V98I) that destabilize HSP60 oligomeric integrity cause hereditary spastic paraplegia (SPG13) and hypomyelinating leukodystrophy, and homozygous knockout is embryonic lethal in mice (PMID:32766281, PMID:20393889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1989 High

    The foundational question of whether mitochondrial protein folding requires a dedicated catalyst was answered: HSP60 mediates ATP-dependent folding of imported mitochondrial proteins, establishing it as the first defined intracellular chaperonin.

    Evidence In vitro import and folding assays in isolated yeast mitochondria plus cDNA cloning confirming mammalian homology to GroEL

    PMID:2528694 PMID:2568584

    Open questions at the time
    • Substrate range of mitochondrial HSP60 undefined
    • Mechanism of ATP coupling to folding unknown
    • Co-chaperonin requirement not yet addressed
  2. 1990 High

    Whether HSP60 oligomer assembly is spontaneous or assisted was resolved: newly imported HSP60 monomers require pre-existing functional 14-mer complexes for their own assembly, revealing a self-templating oligomerization mechanism.

    Evidence Import into mitochondria from hsp60-defective yeast mutant mif4 with pulse-chase assembly kinetics

    PMID:1978929

    Open questions at the time
    • Structural basis of assisted assembly unknown
    • Stoichiometric requirements for template not defined
  3. 1997 High

    The complete chaperonin reaction cycle was delineated: substrate capture at hydrophobic apical sites, ATP-driven encapsulation with HSP10/GroES forming a cis ternary complex, folding in the sealed cavity, ATP hydrolysis priming release, and trans-ring ATP binding dismantling the complex for iterative recycling.

    Evidence Crystallography, cryo-EM, ATPase assays, and mutational analysis across multiple laboratories synthesized into a unified mechanism

    PMID:9098884 PMID:9759498

    Open questions at the time
    • How the cavity environment actively promotes folding (beyond passive confinement) was unresolved
    • Mammalian-specific differences from GroEL not yet characterized
  4. 1999 High

    HSP60's role was extended beyond canonical folding to apoptosis regulation: HSP60 and HSP10 form a mitochondrial complex with pro-caspase-3 and accelerate its activation by cytochrome c in vitro, establishing HSP60 as a direct participant in caspase-dependent cell death.

    Evidence Co-immunoprecipitation from mitochondrial fractions and reconstituted in vitro caspase activation assay

    PMID:10205158

    Open questions at the time
    • Whether HSP60 promotes or inhibits apoptosis appeared context-dependent and unresolved
    • Mechanism of HSP60 release from mitochondria unknown
  5. 2005 Medium

    The scope of HSP60's anti-apoptotic partnerships was broadened: cytosolic HSP60 complexes with Bax, Bak, and Bcl-XL in cardiac cells, and mitochondrial HSP60 interacts with mortalin/mtHsp70, with knockdown of either protein arresting cancer cell growth.

    Evidence Co-immunoprecipitation, subcellular fractionation, siRNA knockdown in cardiac and cancer cell lines

    PMID:15784164 PMID:15957980

    Open questions at the time
    • Direct vs. indirect nature of Bax/Bak binding not resolved
    • Functional consequence of mortalin–HSP60 interaction on specific substrates unclear
    • Whether HSP60 chaperone activity is required for these interactions not tested
  6. 2007 High

    Two outstanding questions were answered: how HSP60 reaches the extracellular space and what it does there. HSP60 is released via exosomes from cardiac myocytes, and separately, HSP60 stabilizes mitochondrial survivin and restrains p53, with siRNA depletion activating caspase-dependent apoptosis in tumor cells.

    Evidence Exosome isolation with EM and pathway inhibitor studies; proteomics screening with Co-IP and siRNA knockdown

    PMID:17307989 PMID:18086682

    Open questions at the time
    • Signals triggering exosomal HSP60 loading unknown
    • Whether HSP60–p53 interaction is direct or chaperoning-dependent not distinguished
  7. 2008 Medium

    Patient-derived cells carrying the SPG13-associated V98I mutation revealed a compensatory cellular adaptation: reduced HSP60 function led to decreased Lon and ClpP protease expression, suggesting cells modulate quality-control protease levels in response to impaired chaperoning.

    Evidence qRT-PCR and Western blot in lymphoblastoid and fibroblast lines from an SPG13 patient heterozygous for HSPD1 c.292G>A

    PMID:18378094

    Open questions at the time
    • Single patient study limits generalizability
    • Causality between reduced HSP60 and protease downregulation not formally established
    • Whether this compensation is neuroprotective or pathological unknown
  8. 2010 High

    The question of whether HSP60 is essential in mammals was definitively answered: homozygous Hspd1 knockout causes embryonic lethality at E6.5–7.5 in mice, while heterozygotes survive with reduced HSP60/HSP10 levels.

    Evidence Gene-trap knockout mouse with genotyping, qRT-PCR, and Western blot

    PMID:20393889

    Open questions at the time
    • Which specific mitochondrial substrates fail to fold and cause lethality unknown
    • Whether extra-mitochondrial HSP60 functions contribute to the lethal phenotype not tested
  9. 2013 High

    Extracellular HSP60 was shown to function as a danger-associated molecular pattern (DAMP): it drives inflammatory cytokine production via TLR4–MyD88–p38/NF-κB signaling in cardiomyocytes, and MnSOD was identified as a specific mitochondrial folding substrate whose impairment under HSP60 haploinsufficiency increases neuronal oxidative stress.

    Evidence TLR blocking antibodies and pathway inhibitors with in vivo LAD ligation; Co-IP and enzymatic activity assays in heterozygous knockout mouse

    PMID:23447644 PMID:24151936

    Open questions at the time
    • Structural basis of HSP60–TLR4 recognition not determined
    • Whether MnSOD misfolding is the primary driver of neurodegeneration in SPG13 not established
  10. 2015 High

    A key structural distinction of mammalian HSP60 from bacterial GroEL was established: wild-type HSP60 exists as single heptameric rings in the apo state and transitions to double-ring football complexes with HSP10 only upon ATP binding, with ATP hydrolysis driving dissociation back to single rings.

    Evidence TEM, native PAGE, and gel filtration of purified porcine HSP60; complemented by native MS, DLS, and analytical ultracentrifugation

    PMID:26427351 PMID:29415503

    Open questions at the time
    • Whether single-ring forms have independent folding activity unknown
    • Physiological triggers controlling the single-to-double ring transition in vivo not identified
  11. 2017 High

    Chemical biology approaches identified specific mitochondrial folding substrates: HSP60 inhibition by myrtucommulone A caused aggregation of LONP and LRP130, directly demonstrating their dependence on HSP60 for proper folding.

    Evidence Affinity pulldown with chemical probe; malate dehydrogenase refolding assay; 2D gel electrophoresis with MS identification of aggregated proteins in isolated mitochondria

    PMID:28457707

    Open questions at the time
    • Complete substrate repertoire of mammalian HSP60 remains undefined
    • Whether substrate selectivity differs between single-ring and double-ring forms unknown
  12. 2018 High

    The physical mechanism by which the chaperonin cavity promotes folding was refined: encapsulation alone (without iterative cycling) repairs defined folding defects through equilibrium confinement-driven chain compaction, and GroEL rings undergo transient separation driven by inter-ring negative allostery that is required for efficient substrate processing in vivo.

    Evidence HX-MS of cavity-encapsulated MBP mutant; FRET-based ring exchange assays with engineered GroEL mutant plus in vivo growth complementation

    PMID:29295923 PMID:29336887

    Open questions at the time
    • Whether mammalian HSP60 single-ring forms undergo analogous ring dynamics unknown
    • Extent to which confinement versus active unfolding contributes under physiological substrate loads not quantified
  13. 2020 High

    Disease mechanism was clarified at the structural level: cryo-EM of apo human HSP60 confirmed single-ring architecture with increased apical-domain flexibility relative to GroEL, and SPG13/leukodystrophy mutations D29G and V98I were shown to destabilize oligomeric integrity rather than monomer folding.

    Evidence Cryo-EM 3D reconstruction of human HSP60; biophysical characterization of purified mutant proteins with native gel and thermal stability assays

    PMID:32766281 PMID:33506187

    Open questions at the time
    • Atomic-resolution structure of human HSP60–HSP10–ATP football complex not yet determined
    • How oligomeric destabilization specifically affects neuronal vulnerability in SPG13 not mechanistically explained
  14. 2021 High

    HSP60's essentiality for mitochondrial oxidative phosphorylation and its druggability were demonstrated: HSPD1 knockout or pharmacological inhibition collapses OXPHOS and suppresses cancer cell proliferation, and arsenic trioxide directly binds HSP60, abolishing refolding activity and disrupting HSP60–p53 and HSP60–survivin complexes.

    Evidence CRISPR knockout plus KHS101 inhibition with Seahorse metabolic profiling and genome-wide CRISPR drug-sensitivity screen; organoarsenic chemical proteomics with cellular thermal shift assay

    PMID:34364401 PMID:34476069

    Open questions at the time
    • Therapeutic window for HSP60 inhibition in cancer versus toxicity to normal tissues not defined
    • Which OXPHOS complex subunits are direct HSP60 folding clients not identified
  15. 2022 High

    Single-molecule experiments revealed that GroEL/ES accelerates folding by actively strengthening polypeptide chain collapse via contractile forces drawing substrates into the cavity, a mechanism distinct from both passive steric confinement and iterative unfolding models.

    Evidence Integrated optical tweezers with single-molecule fluorescence imaging across defined nucleotide states

    PMID:35245117

    Open questions at the time
    • Whether mammalian HSP60 exerts equivalent contractile forces on substrates not tested
    • Structural basis of force generation at the apical domain not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions remain: the complete substrate repertoire of mammalian HSP60 in vivo, the atomic-resolution structure of the human HSP60–HSP10–ATP complex, the mechanistic basis of tissue-specific vulnerability (particularly neuronal) to HSP60 deficiency, and whether the single-ring-to-double-ring transition is regulated by signals beyond ATP availability.
  • No comprehensive substrate catalog for mammalian HSP60 exists
  • High-resolution human HSP60–HSP10–substrate ternary complex structure not determined
  • Cell-type-specific regulation of HSP60 ring dynamics not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 6 GO:0140657 ATP-dependent activity 5 GO:0003924 GTPase activity 1
Localization
GO:0005739 mitochondrion 7 GO:0005829 cytosol 4 GO:0005576 extracellular region 2 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1643685 Disease 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1
Partners
BAXBIRC5CASP3CTNNB1HSPA9HSPE1TP53YBX1
Complex memberships
HSP60–HSP10 chaperonin complexHSP60–mortalin/mtHsp70 complexHSP60–survivin–p53 mitochondrial complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 Mitochondrial Hsp60 is required for the folding of proteins imported into mitochondria; folding occurs at the surface of Hsp60 in an ATP-hydrolysis-dependent reaction followed by release of the bound polypeptide, establishing Hsp60 as an ATP-dependent protein-folding catalyst in the mitochondrial matrix. In vitro import and folding assays in isolated yeast mitochondria; biochemical reconstitution Nature High 2528694
1989 The primary structure of human mitochondrial HSP60 (P1) shows 40–50% sequence identity to bacterial GroEL, the mycobacterial 65 kDa antigen, and the chloroplast rubisco-binding protein, establishing HSP60 as the mammalian chaperonin homolog and suggesting a conserved posttranslational assembly role. cDNA cloning and sequence analysis; amino acid sequence alignment Molecular and cellular biology High 2568584
1990 Hsp60 monomers require pre-existing functional Hsp60 14-mer complexes for their own assembly into new 14-mer rings after mitochondrial import; assembly of newly imported subunits occurs with a half-time of 5–10 min and is thus a catalysed (not spontaneous) reaction. In vitro import into isolated mitochondria from hsp60-defective yeast mutant mif4; pulse-chase assembly assays; biochemical fractionation Nature High 1978929
1992 Murine Hsp60 physically associates with p21ras in intact cells, as demonstrated by chemical cross-linking under conditions where mitochondrial Hsp60 release does not alter the amount complexed to p21ras, suggesting a physiological cytosolic interaction between Hsp60 and Ras. Chemical cross-linking followed by co-immunoprecipitation; cDNA cloning and partial amino acid sequencing to identify the 60 kDa binding partner Proceedings of the National Academy of Sciences of the United States of America Medium 1347942
1997 GroEL/Hsp60-mediated folding operates through: (1) binding of nonnative polypeptides at hydrophobic apical-domain sites, (2) ATP-binding-triggered conformational changes that encapsulate the substrate with GroES/Hsp10 in a cis ternary complex, (3) folding inside the sequestered cavity, (4) ATP hydrolysis in the cis ring priming product release, and (5) ATP binding to the trans ring dismantling the cis complex—enabling iterative recycling of non-native substrates. Structural crystallography, cryo-EM, biochemical ATPase assays, mutational analysis — comprehensive mechanistic review synthesizing multiple experimental approaches Protein science : a publication of the Protein Society High 9098884
1998 The GroEL-GroES complex undergoes major asymmetric conformational changes upon ATP binding: apical domain twisting removes hydrophobic substrate-binding sites from the cavity lining and creates a hydrophilic folding chamber; ATP hydrolysis is not needed for a single round of encapsulation but is required for trans-ring ATP binding to dismantle the cis complex and release substrate. X-ray crystallography of GroEL·GroES·(ADP)7 complex; cryo-EM of allosteric states; biochemical ATPase assays Annual review of biochemistry High 9759498
1999 Pro-caspase-3 is present in mitochondria in a complex with Hsp60 and Hsp10; upon induction of apoptosis, pro-caspase-3 dissociates from the Hsps, which are released from mitochondria. Recombinant Hsp60 and Hsp10 accelerate activation of pro-caspase-3 by cytochrome c and dATP in an ATP-dependent manner in vitro. Co-immunoprecipitation from mitochondrial fractions; in vitro caspase activation assay with recombinant proteins; subcellular fractionation; Western blot The EMBO journal High 10205158
2004 GroEL induces structural rearrangements in a nonnative RuBisCO intermediate: it first partially unfolds or expands the substrate upon capture, then spatially constricts it within the GroEL-GroES cavity, driving the substrate toward compact, folding-competent states. This two-step mechanism (expansion then compression) is ATP- and GroES-dependent. Fluorescence resonance energy transfer (FRET) between amino- and carboxy-terminal domains of RuBisCO; low-temperature trapping of monomeric non-aggregating intermediate; kinetic reactivation assays Molecular cell High 15469819
2005 Mortalin/mtHsp70 and HSP60 interact both in vivo and in vitro; the N-terminal region of mortalin mediates this interaction. Both proteins co-localize in mitochondria, and suppression of HSP60 expression causes cancer cell growth arrest similar to mortalin suppression. Co-immunoprecipitation in vivo and in vitro; shRNA-mediated knockdown; immunofluorescence co-localization The Biochemical journal Medium 15957980
2007 HSP60 is released from adult cardiac myocytes via the exosomal pathway; within exosomes, HSP60 is tightly attached to the exosomal membrane. The classic Golgi-mediated secretory pathway is not responsible for HSP60 release. Exosome isolation; electron microscopy; Western blot of exosomal fractions; pathway inhibitor studies ruling out classical secretion American journal of physiology. Heart and circulatory physiology High 17307989
2007 Hsp60 maintains a mitochondrial pool of survivin (stabilizing it) and forms a complex with p53 that restrains p53 function; siRNA ablation of Hsp60 destabilizes mitochondrial survivin, disrupts the Hsp60-p53 complex causing p53 stabilization, increases pro-apoptotic Bax expression, and activates caspase-dependent apoptosis selectively in tumor cells. High-throughput proteomics screening; siRNA knockdown; Co-immunoprecipitation; mitochondrial fractionation; caspase activity assays The Journal of biological chemistry High 18086682
2009 HSP60 interacts with β-catenin via its apical domain, increases β-catenin protein levels, and enhances β-catenin transcriptional activity to promote metastatic phenotypes in vitro and in vivo; siRNA-mediated repression of β-catenin reverts HSP60-induced metastasis, and this effect is independent of proteasomal activity. Co-immunoprecipitation; overexpression and siRNA knockdown; in vitro invasion assays; in vivo metastasis assays; domain mapping Carcinogenesis Medium 19369584
2009 HSP60 interacts with YB-1 at the YB-NLS region in the cytoplasm; this interaction regulates the polysome association and subcellular distribution of YB-1: knockdown of HSP60 increases polysome-associated YB-1, while HSP60 overexpression decreases YB-1 in heavy-sedimenting polysome fractions and suppresses YB-NLS nuclear translocation activity. Co-immunoprecipitation; sucrose gradient sedimentation; siRNA knockdown; overexpression; subcellular fractionation Biochemical and biophysical research communications Medium 19470374
2010 Homozygous inactivation of the Hspd1 gene in mice causes early embryonic lethality shortly after implantation (E6.5–7.5), demonstrating that Hspd1 is an essential gene for mammalian embryonic development; heterozygous mice show reduced Hsp60 and Hsp10 protein levels but survive normally. Gene-trap mouse knockout; genotyping; quantitative RT-PCR; Western blot; embryo staging Cell stress & chaperones High 20393889
2013 Extracellular HSP60 induces inflammatory cytokine production in cardiomyocytes via TLR4–MyD88–p38/NF-κB signaling, and upregulates TLR2/4 expression via TLR4–MyD88–JNK/NF-κB signaling. During ischemia, endogenous HSP60 released extracellularly triggers the same pathways to promote myocardial inflammation. Cytokine ELISA; TLR blocking antibodies; pathway inhibitors (p38, JNK, NF-κB); siRNA for MyD88/TLR4; rat LAD ligation model Cardiovascular research High 23447644
2013 Hsp60 interacts with manganese superoxide dismutase (MnSOD) and is required for proper MnSOD folding; in a heterozygous Hsp60-knockout mouse model, reduced Hsp60 availability leads to impaired MnSOD function and increased oxidative stress in neuronal tissues, identifying MnSOD as a substrate of the Hsp60 folding machinery. Co-immunoprecipitation; heterozygous knockout mouse model; ROS measurements; enzymatic activity assays for MnSOD Free radical research Medium 24151936
2014 The GroEL-GroES2 'football' complex (symmetric, both rings capped) is the protein-folding functional form. Substrate protein-catalyzed ADP/ATP exchange enables both chambers to encapsulate substrate efficiently when substrate binding precedes ATP. The two rings of GroEL function as a parallel processing machine in this form, differing conformationally from the asymmetric 'bullet' complex at both the GroEL-GroES interface and the inter-ring interface. Cryo-EM structure determination (~3.7 Å); calibrated FRET; order-of-addition biochemical experiments Proceedings of the National Academy of Sciences of the United States of America High 25136110
2015 FUS (ALS/FTLD-associated RNA-binding protein) interacts with HSP60 and uses this interaction to translocate to mitochondria; downregulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS in transgenic Drosophila. Co-immunoprecipitation; biochemical fractionation; HSP60 siRNA knockdown; transgenic Drosophila genetics; mitochondrial morphology assays PLoS genetics Medium 26335776
2015 Gold(III) porphyrin (gold-1a) directly targets and inhibits Hsp60 chaperonin activity in vitro and in cells; inhibition of Hsp60 by gold-1a depends on both the gold(III) ion and the porphyrin ligand working together, as shown by structure-activity studies with non-porphyrin gold(III) complexes and other metalloporphyrins. Photo-affinity labeling; click chemistry; chemical proteomics; cellular thermal shift assay; saturation-transfer difference NMR; protein fluorescence quenching; protein chaperone refolding assay Angewandte Chemie (International ed. in English) High 26663758
2015 Mitochondrial Lon protease associates with the Hsp60-mtHsp70 chaperone complex; Lon maintains protein stability/levels of the Hsp60-mtHsp70 complex under oxidative stress, and Lon's ability to inhibit apoptosis depends on Hsp60 binding to p53. Co-immunoprecipitation; shotgun mass spectrometry interactome; immunofluorescence co-localization; siRNA knockdown; apoptosis assays Cell death & disease Medium 25675302
2015 Wild-type mammalian HSP60 forms heptameric single-ring structures in the absence of ATP, but forms predominantly football-type (symmetric double-ring) complexes with HSP10 in the presence of ATP. After ATP hydrolysis to ADP, HSP60 releases HSP10 and the double-ring dissociates to single rings, demonstrating an ATP-dependent single-ring ↔ double-ring transition distinct from the bacterial GroEL/GroES cycle. Purification from porcine liver; transmission electron microscopy; native PAGE; gel filtration; protein refolding assay Archives of biochemistry and biophysics High 26427351
2017 Myrtucommulone A (MC) directly binds HSP60 and inhibits its protein refolding activity; HSP60 inhibition by MC leads to aggregation of Lon protease-like protein (LONP) and leucine-rich PPR motif-containing protein (LRP130) in isolated mitochondria, identifying these as HSP60-dependent substrates. Protein fishing/affinity pulldown with MC as bait; protein refolding assay (malate dehydrogenase); 2D gel electrophoresis and MS identification of aggregated proteins in isolated mitochondria Cell chemical biology High 28457707
2017 HSP60 possesses GTPase activity in addition to its established ATPase activity; GTP alters HSP60 allostery, complex formation with HSP10, and protein folding activity differently than ATP, providing evidence for nucleotide-dependent functional modulation of the HSP60-HSP10 complex. GTPase activity assay; ATPase assay; native PAGE; protein folding reactivation assay Scientific reports Medium 29208924
2017 miR-382 targets the 3′-UTR of HSPD1 mRNA, downregulating HSP60 protein expression; HSPD1 knockdown promotes oxidative stress by reducing thioredoxin (Trx) expression, while HSPD1 overexpression restores Trx levels and reverses TGF-β1-induced loss of E-cadherin, placing HSPD1 upstream of the Trx antioxidant pathway in renal fibrosis. miR-382 mimic/anti-miR; HSPD1 siRNA knockdown; HSPD1 overexpression; luciferase reporter (3′-UTR target validation); UUO mouse model; Western blot; redox markers Oxidative medicine and cellular longevity Medium 28680529
2018 Mammalian HSP60 undergoes nucleotide-dependent assembly: HSP10 binding promotes HSP60 double-ring formation in the presence of ATP; after ATP hydrolysis to ADP, HSP10 is released and double-rings dissociate to single rings. This structural transition is highly distinctive from GroEL/GroES, particularly in complex formation mode and the roles of ATP binding versus hydrolysis. Multiple analytical techniques under near-physiological conditions: native MS, DLS, analytical ultracentrifugation, fluorescence; ATP/ADP titration experiments International journal of molecular sciences High 29415503
2018 GroEL undergoes transient ring separation (ring exchange between complexes) upon ATP binding to the trans ring, driven by inter-ring negative allostery. A GroEL mutant unable to perform ring separation remains folding-active but populates symmetric GroEL:GroES2 football complexes where both rings function simultaneously rather than sequentially, leading to inefficient substrate binding/release and impaired E. coli growth. FRET-based ring exchange assay; GroEL ring-separation mutant; in vivo E. coli growth complementation; native gel electrophoresis Cell High 29336887
2018 Simple encapsulation of maltose binding protein (MBP) within the GroEL/ES cavity repairs a defined folding defect (V9G mutation that disrupts a preintermediate hydrophobic cluster) and restores wild-type folding rates, with or without ATP-driven cycling. This reveals a folding mechanism based on nonspecific equilibrium compression/confinement within the cavity rather than unfolding of misfolded intermediates. Hydrogen exchange-mass spectrometry (HX-MS); fluorescence refolding kinetics; site-directed mutagenesis; comparison of free-solution vs. cavity-encapsulated folding Proceedings of the National Academy of Sciences of the United States of America High 29295923
2019 HSP60-survivin complexes exist in both cytosolic and mitochondrial compartments in a cell-type-dependent manner. In mitochondria, HSP60 promotes survival by stabilizing survivin and interacting with CCAR2 and p53. When HSP60 is released from mitochondria to cytosol upon death stimuli, it can promote apoptosis by stabilizing Bax, enhancing pro-caspase-3 activation, or increasing protein ubiquitination. Subcellular fractionation; Co-immunoprecipitation; siRNA knockdown; apoptosis assays; literature synthesis with mechanistic framework Cells Medium 31861751
2020 Cryo-EM structure of human mitochondrial HSPD1 in the apo state reveals that, unlike bacterial GroEL (which exists as double rings), HSPD1 forms mostly single-ring assemblies in the absence of co-chaperonin HSPE1. Comparison with GroEL shows a rotation and increased flexibility of the apical domain in HSPD1. Cryo-electron microscopy; 3D reconstruction and comparison with GroEL structures iScience High 33506187
2020 Disease-associated point mutations in HSPD1 (D29G and V98I linked to hereditary spastic paraplegia/hypomyelinating leukodystrophy) act primarily by destabilizing the oligomeric stability of the mtHsp60 complex rather than globally unfolding the monomer, suggesting oligomeric integrity is essential for folding function and neuronal survival. Biophysical characterization of purified mutant proteins; native gel electrophoresis; thermal stability assays; structural modeling; literature synthesis Frontiers in molecular biosciences Medium 32766281
2021 HSPD1 knockdown or chemical disruption by small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation (OXPHOS) and suppresses NSCLC proliferation in vitro and in vivo. A genome-wide CRISPR/Cas9 screen validated that KHS101 anti-cancer effects are dependent on OXPHOS, with SLC6A8 (creatine transporter) and COX5B (cytochrome c oxidase subunit) as determinants of sensitivity. HSPD1 CRISPR/Cas9 knockout; siRNA knockdown; KHS101 pharmacological inhibition; extracellular metabolic flux analysis (Seahorse); genome-wide CRISPR/Cas9 drug sensitivity screen; in vivo xenograft Journal of experimental & clinical cancer research : CR High 34364401
2021 Arsenic trioxide (ATO) binds directly to Hsp60 and abolishes its protein refolding capability; ATO binding disrupts the Hsp60-p53 and Hsp60-survivin complexes, resulting in degradation of both p53 and survivin in APL cells. Organoarsenic chemical probe metalloproteomics; quantitative proteomics; cellular thermal shift assay; biophysical binding assays; cell-based p53/survivin stability assays; protein refolding assay Chemical science High 34476069
2022 GroEL-ES accelerates protein folding by strengthening polypeptide chain collapse: GroEL induces contractile forces in substrate chains drawing them into the cavity and triggering compaction and discrete folding transitions. Collapse enhancement is strongest in nucleotide-bound states, aided by GroES at the cavity rim and amphiphilic C-terminal tails at the cavity bottom. This mechanism is distinct from steric confinement and misfold-unfolding mechanisms. Integrated optical tweezers protein manipulation; single-molecule fluorescence imaging; nucleotide state-specific measurements; GroES binding assays Science advances High 35245117
2008 Patient cells heterozygous for the c.292G>A HSPD1 allele encoding Hsp60-p.Val98Ile show decreased expression of mitochondrial proteases Lon and ClpP at both RNA and protein levels, suggesting a compensatory cellular adaptation to reduced Hsp60 chaperonin activity that allows substrate proteins more folding attempts before degradation. qRT-PCR; Western blot; mitochondrial membrane potential; oxidative stress assays in lymphoblastoid and fibroblast cell lines from SPG13 patient Neuroscience Medium 18378094
2005 Cytosolic HSP60 in cardiac cells forms complexes with Bax, Bak, and Bcl-XL (but not Bcl-2) under normal conditions; during hypoxia, HSP60 redistributes from cytosol to the plasma membrane, coinciding with cytochrome c release from mitochondria prior to reoxygenation. Reduction in HSP60 expression precipitates apoptosis without altering mitochondrial function. Additionally, HSP60 accelerates cleavage of pro-caspase-3. Co-immunoprecipitation; subcellular fractionation; siRNA knockdown; hypoxia-reoxygenation model; immunofluorescence Journal of cellular and molecular medicine Medium 15784164

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Biological insights from 108 schizophrenia-associated genetic loci. Nature 5878 25056061
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2005 Nucleolar proteome dynamics. Nature 934 15635413
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2016 An improved smaller biotin ligase for BioID proximity labeling. Molecular biology of the cell 665 26912792
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
1989 Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis. Nature 576 2528694
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
1989 Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Molecular and cellular biology 479 2568584
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2020 Mechanical regulation of glycolysis via cytoskeleton architecture. Nature 445 32051585
2003 TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 442 12887919
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1999 Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. The EMBO journal 438 10205158
1998 Structure and function in GroEL-mediated protein folding. Annual review of biochemistry 436 9759498
1997 GroEL-mediated protein folding. Protein science : a publication of the Protein Society 313 9098884
2007 HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. American journal of physiology. Heart and circulatory physiology 299 17307989
1995 Evolution of the chaperonin families (Hsp60, Hsp10 and Tcp-1) of proteins and the origin of eukaryotic cells. Molecular microbiology 230 7752884
2007 Hsp60 regulation of tumor cell apoptosis. The Journal of biological chemistry 223 18086682
2001 GroEL (Hsp60) of Clostridium difficile is involved in cell adherence. Microbiology (Reading, England) 174 11160803
1990 The mitochondrial chaperonin hsp60 is required for its own assembly. Nature 169 1978929
1993 Sequence homologies between hsp60 and autoantigens. Immunology today 163 8466626
2015 FUS Interacts with HSP60 to Promote Mitochondrial Damage. PLoS genetics 155 26335776
2005 HSP60, Bax, apoptosis and the heart. Journal of cellular and molecular medicine 145 15784164
2012 Structure and allostery of the chaperonin GroEL. Journal of molecular biology 141 23183375
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