{"gene":"HSPE1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1990,"finding":"Mitochondrial cpn10 (HSP10/HSPE1 homologue) was identified in beef and rat liver mitochondria as functionally equivalent to E. coli GroES; it forms a stable complex with bacterial cpn60 in the presence of Mg·ATP, competes with bacterial cpn10 for a common saturable site on cpn60, and virtually abolishes the 'uncoupled ATPase' activity of cpn60 upon complex formation, thereby facilitating ATP/K+-dependent discharge of unfolded substrate protein from cpn60.","method":"In vitro reconstitution of RuBisCO refolding, ATPase inhibition assay, stable complex formation with Mg·ATP, competition binding","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro reconstitution assays (refolding, ATPase inhibition, complex formation, competition) establishing functional equivalence and direct physical interaction","pmids":["1977163"],"is_preprint":false},{"year":1994,"finding":"Yeast mitochondrial Hsp10 (HSPE1 orthologue) is an essential component of the mitochondrial protein-folding apparatus; temperature-sensitive hsp10 mutants fail to fold and assemble proteins imported into the matrix compartment and are also required for sorting of the Rieske Fe/S protein through the matrix. The temperature-sensitive mutations map to the mobile loop region (residues 25–40) and result in reduced binding affinity for Hsp60 at the non-permissive temperature.","method":"Yeast genetics (temperature-sensitive lethal mutants), import/folding assays, biochemical fractionation, site mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with defined folding and sorting phenotypes, plus domain-level mutagenesis identifying the mobile loop as critical for Hsp60 binding","pmids":["7913473"],"is_preprint":false},{"year":1998,"finding":"Yeast mitochondrial in vivo substrates fall into three groups: (i) proteins requiring both Hsp60 and Hsp10 for folding; (ii) proteins that fail to fold without Hsp60 but are unaffected by Hsp10 inactivation; (iii) newly imported Hsp60 itself, which is more severely affected by Hsp10 inactivation than by loss of pre-existing Hsp60. This demonstrates that Hsp10 and Hsp60 do not always act as a single functional unit in vivo.","method":"Novel in vivo substrate screen in S. cerevisiae using temperature-sensitive hsp60 and hsp10 mutants, molecular weight determination of ~15–90 kDa substrates","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic screen with two independent conditional mutants and multiple substrates, revealing differential chaperonin requirements","pmids":["9774331"],"is_preprint":false},{"year":2001,"finding":"Overexpression of HSP60 and HSP10 (individually or in combination) in rat neonatal cardiac myocytes protected against simulated ischemia/reoxygenation-induced apoptosis, reducing mitochondrial cytochrome c release, caspase-3 activation, and maintaining ATP levels through preserved electron transport chain complex III and IV activities.","method":"Adenoviral overexpression in primary cardiomyocytes, enzyme release/DNA fragmentation/caspase-3 assays, mitochondrial ETC activity measurements, ATP quantification","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression with multiple functional readouts (apoptosis, ETC activity, ATP), single lab","pmids":["11282911"],"is_preprint":false},{"year":2003,"finding":"Overexpression of Hsp10 or Hsp60 in cardiomyocytes suppressed doxorubicin-induced apoptosis by differentially modulating Bcl-2 family members; both proteins increased Bcl-xl and Bcl-2 and reduced Bax at the post-translational level by inhibiting ubiquitination of Bcl-xl (shown to be cycloheximide-insensitive and mRNA-independent). Hsp60 additionally interacted with Bcl-xl and Bax by co-immunoprecipitation in vivo.","method":"Adenoviral overexpression in primary cardiomyocytes, co-immunoprecipitation, cycloheximide chase, ubiquitination assay, antisense Hsp60 knockdown","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP for Hsp60-Bcl-xl/Bax interaction, multiple functional readouts, single lab; Hsp10-specific interaction with Bcl family not shown by co-IP","pmids":["12967636"],"is_preprint":false},{"year":2003,"finding":"Hsp10 and Hsp60 overexpression in cardiomyocytes increased IGF-1 receptor (IGF-1R) abundance and IGF-1-stimulated autophosphorylation by suppressing polyubiquitination of IGF-1R, a post-translational mechanism independent of protein synthesis or mRNA upregulation. Conversely, antisense Hsp60 knockdown decreased IGF-1R abundance and attenuated IGF-1R signaling and pro-survival actions.","method":"Adenoviral overexpression/antisense knockdown in neonatal cardiomyocytes, ubiquitination assay, cycloheximide chase, phosphorylation assays for IGF-1R and downstream kinases","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (ubiquitination assay, cycloheximide chase, signaling readouts), single lab; Hsp10 role inferred from overexpression without direct binding demonstration","pmids":["12970367"],"is_preprint":false},{"year":2004,"finding":"Hsp10 protection of cardiac myocytes against simulated ischemia/reoxygenation requires its mobile loop (a P34H mobile-loop mutant incapable of co-refolding malate dehydrogenase with Hsp60 potentiated cell death). Protection involves preservation of mitochondrial complex I and II function and requires inactivation of the Ras GTPase pathway; Hsp10 overexpression inactivated Raf, ERK, and p90RSK, and constitutively active Ras abolished Hsp10-mediated protection.","method":"Adenoviral overexpression of wild-type and P34H mutant Hsp10, ETC complex activity assays, Ras pathway inhibitor studies, constitutively active Ras co-expression","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-function mutagenesis (mobile loop mutant) combined with pathway epistasis (Ras inhibitor, constitutively active Ras), single lab","pmids":["15059967"],"is_preprint":false},{"year":2002,"finding":"The human HSP60 (HSPD1) and HSP10 (HSPE1) genes are arranged head-to-head on chromosome 2q33.1, separated by a bidirectional promoter (~17 kb total); luciferase reporter assays demonstrated bidirectional promoter activity that increases ~12-fold upon heat shock in both directions, with a STAT3-binding site identified as a regulatory element.","method":"Genomic sequencing, radiation hybrid mapping, luciferase reporter assay, heat-shock induction","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional promoter assay with deletion/mutation analysis, single lab","pmids":["12483302"],"is_preprint":false},{"year":2007,"finding":"NO (from iNOS) downregulates HSP60 and HSP10 expression in the postischemic brain by suppressing STAT3 binding to its recognition site in the bidirectional promoter; reporter gene analysis with deletion and mutation studies identified the STAT3 site as responsible for LPS/IFN-γ-induced upregulation and for NO-mediated downregulation.","method":"Middle cerebral artery occlusion mouse model, iNOS inhibitor (aminoguanidine), C6 astroglioma cell LPS/IFN-γ treatment, iNOS inhibitor NMMA, luciferase reporter with promoter deletion/mutation","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter gene with deletion/mutation analysis identifying STAT3 site, confirmed in vivo and in vitro, single lab","pmids":["17348040"],"is_preprint":false},{"year":2015,"finding":"Mitochondrial Hsp70 (mtHsp70) associates with Hsp10 independently of Hsp60; the mtHsp70–Hsp10 complex binds to unassembled Hsp60 precursor and promotes its assembly into mature heptameric Hsp60 complexes. This places HSPE1 as a co-factor for Hsp60 biogenesis in addition to its folding co-chaperonin role.","method":"Comprehensive interaction study by MS-based co-immunoprecipitation in yeast mitochondria, including controls separating Hsp70–Hsp10 interaction from Hsp60","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome with multiple co-IP controls establishing independent Hsp10–Hsp70 interaction, single lab","pmids":["25792736"],"is_preprint":false},{"year":2016,"finding":"A de novo missense mutation in HSPE1 (c.217C>T, p.Leu73Phe) causes near-complete loss of the mutant HSP10 protein in patient fibroblasts (detected by mass spectrometry), resulting in an ~2-fold decrease in the HSP10:HSP60 ratio, ~80% reduction of SOD2 protein (a known HSP60/HSP10 substrate) without change in SOD2 mRNA, and ~2-fold increase in mitochondrial superoxide levels. In vitro, the purified mutant protein had profoundly impaired thermal stability, refolding propensity, and protease resistance.","method":"Clinical exome sequencing, mass spectrometry of patient fibroblasts, in vitro purification and functional characterization of mutant HSP10, mRNA/protein quantification, mitochondrial superoxide measurement","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — combines in vitro biochemical characterization of mutant protein with ex vivo patient fibroblast proteomics and functional consequences, single lab, case study","pmids":["27774450"],"is_preprint":false},{"year":2020,"finding":"Cross-linking immunoprecipitation/MS survey of the human mitochondrial HSP60/HSP10 chaperonin in HEK293 cells identified 323 interacting proteins; ~50% of annotated mitochondrial matrix proteins interact with HSP60/HSP10, covering the respiratory chain, mitochondrial protein synthesis apparatus, and protein quality control. Nineteen abundant matrix proteins occupy >60% of HSP60/HSP10 chaperonin capacity.","method":"Metabolic labeling of HEK293 cells, chemical cross-linking, HSP60 immunoprecipitation, quantitative mass spectrometry","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic MS interactome with cross-linking and quantitative labeling, single lab; broad interactome survey rather than individual mechanistic validation","pmids":["32060690"],"is_preprint":false},{"year":2015,"finding":"HSPE1/Cpn10 (a pool) localizes to the nucleus where it co-localizes with NPAT foci during G1 and S phases. Cpn10 interacts with NPAT (a Cyclin E/CDK2 substrate that regulates histone transcription) via a conserved DLFD motif; knockdown of Cpn10 disrupts NPAT focus formation and reduces histone gene transcription and S-phase progression, while overexpression promotes histone transcription.","method":"Co-immunoprecipitation, confocal co-localization, gain- and loss-of-function (siRNA knockdown, overexpression), motif mutagenesis (DLFD), histone mRNA quantification, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutational dissection of DLFD motif, and multiple functional readouts in a single study; single lab","pmids":["26429916"],"is_preprint":false},{"year":2017,"finding":"Human HSP60 possesses GTPase activity; in the presence of GTP versus ATP, the HSP60-HSP10 complex shows different allosteric properties, complex formation characteristics, and protein folding activity, indicating that nucleotide identity modulates the functional mechanism of the HSP60-HSP10 complex.","method":"In vitro GTPase and ATPase activity assays, protein folding assays with HSP60/HSP10 complex","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro biochemical assay, limited mechanistic detail available from abstract alone","pmids":["29208924"],"is_preprint":false},{"year":2023,"finding":"Depletion of HSPE1 (but not HSPD1) in HEK293T cells causes mitochondrial fragmentation through proteolytic inactivation of OPA1 mediated by the stress-activated metalloprotease OMA1, revealing a chaperonin-activity-independent role of HSPE1 in controlling mitochondrial morphology and fusion.","method":"siRNA knockdown of HSPD1 and HSPE1 in HEK293T cells, mitochondrial morphology imaging, OPA1 processing assay, OMA1 activation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic separation of HSPE1 vs. HSPD1 knockdown with specific mechanistic readout (OMA1/OPA1 cleavage), single lab, two orthogonal phenotypic/biochemical approaches","pmids":["36818283"],"is_preprint":false},{"year":2024,"finding":"Glutamine activates SIRT4 (by increasing NAD+ and SIRT4 protein levels), which deacetylates HSP60 to promote assembly of the HSP60–HSP10 complex in mitochondria; restored complex activity maintains electron transport chain complex II and III function, ATP generation, and reduces reactive oxygen species in hepatocytes under burn sepsis conditions.","method":"In vitro and in vivo burn-sepsis model, NAD+ measurement, SIRT4 protein quantification, HSP60 acetylation assay, ETC complex activity assays, ATP measurement, ROS quantification","journal":"Redox report","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-step mechanistic pathway (Gln→SIRT4→HSP60 deacetylation→HSP60-HSP10 assembly→ETC function) with multiple orthogonal assays, single lab","pmids":["38329114"],"is_preprint":false},{"year":1995,"finding":"GroES (the bacterial HSPE1 homologue) has no affinity for nucleotides: photolabeling of GroES with 8-azido-ATP was found to be non-specific (other non-nucleotide-binding proteins were also labeled), and rigorous isothermal calorimetry and equilibrium binding assays detected no interaction between GroES and nucleotides.","method":"Isothermal calorimetry, equilibrium binding, 8-azido-ATP photolabeling with controls","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — negative result established by two orthogonal rigorous physical methods (ITC + equilibrium binding) correcting a prior claim; mechanistically informative negative finding","pmids":["7867782"],"is_preprint":false},{"year":2006,"finding":"HSP10 is detected in the sera, ascites, and conditioned media of ovarian cancer patients but not controls; immunoprecipitation removal of HSP10 from patient sera diminished the ability to suppress T-cell CD3-zeta expression, while the immunoprecipitate alone suppressed CD3-zeta, identifying secreted HSP10 as a direct suppressor of T-cell activation.","method":"Western immunoblotting of sera/ascites/conditioned media, immunoprecipitation depletion/reconstitution bioassay using Jurkat cells, CD3-zeta expression quantification","journal":"Gynecologic oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited patient numbers (n=10), bioassay with immunodepletion; functional mechanism of CD3-zeta suppression not defined beyond HSP10 presence","pmids":["16386781"],"is_preprint":false}],"current_model":"HSPE1 (HSP10) encodes the mitochondrial co-chaperonin that forms a functional complex with HSP60 (HSPD1) to mediate ATP-dependent protein folding in the mitochondrial matrix via its mobile loop, which binds HSP60 and gates substrate release; independently of this canonical activity, HSPE1 controls mitochondrial morphology by preventing OMA1-mediated OPA1 cleavage, participates in Hsp60 ring assembly together with mtHsp70, modulates post-translational stability of Bcl-2 family members and IGF-1R via ubiquitination suppression in cardiomyocytes, and—in a non-mitochondrial nuclear pool—interacts with NPAT through a conserved DLFD motif to regulate histone gene transcription and S-phase progression."},"narrative":{"mechanistic_narrative":"HSPE1 (HSP10/cpn10) is the mitochondrial co-chaperonin that partners with HSP60 (HSPD1) to drive ATP-dependent folding of matrix proteins, the functional equivalent of bacterial GroES [PMID:1977163]. It binds HSP60 in a Mg·ATP-dependent manner, abolishing the uncoupled ATPase activity of HSP60 to gate discharge of unfolded substrate [PMID:1977163], and this interaction depends on its mobile loop (residues 25–40), where temperature-sensitive mutations reduce HSP60 affinity and abolish folding and matrix sorting in vivo [PMID:7913473]; the same mobile loop is required for HSP10's protective and co-refolding activity, as a P34H mutant cannot co-refold substrate with HSP60 [PMID:15059967]. Genetic dissection shows HSP10 and HSP60 do not always act as one unit, with distinct in vivo substrate classes and a specific requirement for HSP10 in folding newly imported HSP60 itself [PMID:9774331]. Beyond folding, HSPE1 acts as a co-factor for HSP60 biogenesis: an mtHsp70–HSP10 complex, formed independently of HSP60, binds unassembled HSP60 precursor and promotes its assembly into mature heptamers [PMID:25792736], and this assembly is further tuned by SIRT4-mediated deacetylation of HSP60 to maintain electron transport chain function and limit ROS [PMID:38329114]. The HSP60/HSP10 chaperonin engages roughly half of the annotated matrix proteome, including the respiratory chain, mitochondrial translation machinery, and quality-control factors [PMID:32060690], and is human HSP60's catalytic partner whose folding output is modulated by nucleotide identity [PMID:29208924]. HSPE1 also performs chaperonin-independent functions: its depletion (but not that of HSPD1) triggers OMA1-mediated OPA1 cleavage and mitochondrial fragmentation, linking it to mitochondrial morphology and fusion [PMID:36818283], and a nuclear pool interacts with NPAT through a conserved DLFD motif to organize NPAT foci and drive histone gene transcription and S-phase progression [PMID:26429916]. A de novo p.Leu73Phe mutation that destabilizes HSP10 lowers the HSP10:HSP60 ratio, depletes the substrate SOD2, and raises mitochondrial superoxide, establishing HSPE1 as the cause of a human mitochondrial disorder [PMID:27774450].","teleology":[{"year":1990,"claim":"Established that mammalian HSP10 is the functional co-chaperonin of HSP60, defining the core biochemical mechanism of ATP-dependent substrate discharge.","evidence":"In vitro RuBisCO refolding, ATPase inhibition, Mg·ATP-dependent complex formation, and competition binding with bacterial cpn60","pmids":["1977163"],"confidence":"High","gaps":["Did not resolve which residues mediate the HSP60 contact","Performed with bacterial cpn60 rather than mammalian HSP60"]},{"year":1994,"claim":"Showed HSP10 is essential for matrix protein folding and sorting in vivo and pinpointed the mobile loop as the HSP60-binding determinant.","evidence":"Temperature-sensitive hsp10 lethal mutants in yeast with import/folding and Rieske Fe/S sorting assays and site mapping to residues 25-40","pmids":["7913473"],"confidence":"High","gaps":["Did not enumerate the full set of dependent substrates","Structural basis of mobile-loop/HSP60 contact not resolved"]},{"year":1998,"claim":"Revealed that HSP10 and HSP60 are not obligately coupled in vivo, with distinct substrate dependencies including a special role in folding newly imported HSP60.","evidence":"In vivo substrate screen using conditional hsp60 and hsp10 mutants in S. cerevisiae","pmids":["9774331"],"confidence":"High","gaps":["Molecular basis for HSP10-independent HSP60 folding not defined","Substrate identities only resolved by molecular weight"]},{"year":2001,"claim":"Connected HSP10/HSP60 chaperonin function to cytoprotection, showing overexpression preserves respiratory function and blocks ischemic apoptosis.","evidence":"Adenoviral overexpression in rat cardiomyocytes with apoptosis, ETC complex III/IV activity, and ATP readouts","pmids":["11282911"],"confidence":"Medium","gaps":["Could not separate HSP10-specific from HSP60 contributions","Mechanism of cytochrome c retention not defined"]},{"year":2003,"claim":"Identified post-translational, ubiquitination-dependent control of apoptotic and survival factors as a downstream consequence of HSP10/HSP60 expression.","evidence":"Adenoviral overexpression/antisense knockdown in cardiomyocytes with co-IP, cycloheximide chase, and ubiquitination assays for Bcl-2 family and IGF-1R","pmids":["12967636","12970367"],"confidence":"Medium","gaps":["HSP10-specific direct binding to Bcl-xl/Bax/IGF-1R not demonstrated","Identity of the responsible ubiquitin ligase or DUB unknown"]},{"year":2004,"claim":"Demonstrated that HSP10 cytoprotection requires its mobile loop and an intact Ras pathway inactivation step, tying folding capacity to a signaling outcome.","evidence":"Adenoviral wild-type vs P34H mobile-loop mutant Hsp10 with ETC assays and Ras pathway epistasis (inhibitor and constitutively active Ras)","pmids":["15059967"],"confidence":"Medium","gaps":["Mechanism linking chaperonin activity to Ras/Raf/ERK inactivation not defined","Single lab, overexpression-based"]},{"year":2002,"claim":"Defined the genomic and transcriptional control of HSPE1, showing it shares a heat-inducible bidirectional promoter with HSPD1 regulated by a STAT3 site.","evidence":"Genomic mapping and luciferase reporter assays with heat-shock induction at the 2q33.1 locus","pmids":["12483302"],"confidence":"Medium","gaps":["Other transcription factors at the promoter not characterized","Reporter-based, not endogenous chromatin context"]},{"year":2007,"claim":"Extended transcriptional control to a physiological setting, showing NO/iNOS downregulates HSPE1 via the STAT3 promoter element after ischemia.","evidence":"MCAO mouse model with iNOS inhibitors and C6 astroglioma reporter assays with promoter deletion/mutation","pmids":["17348040"],"confidence":"Medium","gaps":["Functional consequence of HSPE1 loss in postischemic brain not measured","Mechanism of NO action on STAT3 not resolved"]},{"year":2015,"claim":"Uncovered a non-mitochondrial nuclear role for HSPE1 in histone gene transcription and S-phase progression through NPAT binding.","evidence":"Reciprocal co-IP, confocal co-localization, DLFD motif mutagenesis, knockdown/overexpression, histone mRNA and cell cycle analysis","pmids":["26429916"],"confidence":"Medium","gaps":["How HSPE1 partitions between mitochondria and nucleus unknown","Whether nuclear function requires chaperonin activity unclear"]},{"year":2015,"claim":"Recast HSPE1 as a co-factor for HSP60 biogenesis, forming an HSP60-independent complex with mtHsp70 that assembles HSP60 heptamers.","evidence":"MS-based co-IP interactome in yeast mitochondria with controls separating Hsp70-Hsp10 from Hsp60","pmids":["25792736"],"confidence":"Medium","gaps":["Stoichiometry and structure of the mtHsp70-HSP10 complex not resolved","Whether this applies in human mitochondria not tested here"]},{"year":2016,"claim":"Provided human disease causation, linking a destabilizing HSPE1 mutation to substrate (SOD2) loss and oxidative stress.","evidence":"Exome sequencing, patient fibroblast mass spectrometry, in vitro mutant characterization, and mitochondrial superoxide measurement","pmids":["27774450"],"confidence":"Medium","gaps":["Single case study","Full clinical spectrum and additional affected substrates not defined"]},{"year":2020,"claim":"Mapped the global substrate landscape of the HSP60/HSP10 chaperonin in human cells, defining its proteostatic scope.","evidence":"Cross-linking HSP60 immunoprecipitation with quantitative mass spectrometry in HEK293 cells","pmids":["32060690"],"confidence":"Medium","gaps":["Does not distinguish obligate clients from transient interactors","HSP10-specific contribution to each interaction not parsed"]},{"year":2023,"claim":"Demonstrated a chaperonin-independent function of HSPE1 in mitochondrial morphology by preventing OMA1-mediated OPA1 cleavage.","evidence":"Selective siRNA knockdown of HSPE1 vs HSPD1 in HEK293T with morphology imaging and OPA1/OMA1 processing assays","pmids":["36818283"],"confidence":"Medium","gaps":["Mechanism by which HSPE1 loss activates OMA1 unknown","Whether mobile loop or chaperonin contacts are involved not tested"]},{"year":2024,"claim":"Showed an upstream regulatory input controlling HSP60-HSP10 assembly via SIRT4-mediated HSP60 deacetylation to sustain respiration.","evidence":"Burn-sepsis in vitro/in vivo model with NAD+, SIRT4, HSP60 acetylation, ETC complex II/III activity, ATP, and ROS measurements","pmids":["38329114"],"confidence":"Medium","gaps":["Direct HSP60 acetylation sites controlling HSP10 binding not mapped","Single disease-model context"]},{"year":null,"claim":"How HSPE1 is partitioned and regulated across its mitochondrial folding, mitochondrial morphology, nuclear histone-transcription, and secreted immunomodulatory roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating mobile-loop folding with non-canonical functions","Mechanism of nuclear/extracellular localization undefined","Secreted HSP10 mechanism of CD3-zeta suppression not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,14]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,9,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12]}],"complexes":["HSP60-HSP10 (cpn60/cpn10) chaperonin","mtHsp70-Hsp10 complex"],"partners":["HSPD1","HSPA9","NPAT","OMA1","OPA1","SIRT4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61604","full_name":"10 kDa heat shock protein, mitochondrial","aliases":["10 kDa chaperonin","Chaperonin 10","CPN10","Early-pregnancy factor","EPF","Heat shock protein family E member 1"],"length_aa":102,"mass_kda":10.9,"function":"Co-chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp60, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix (PubMed:11422376, PubMed:1346131, PubMed:7912672). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein (Probable)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P61604/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HSPE1","classification":"Common Essential","n_dependent_lines":1165,"n_total_lines":1165,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HSPE1","total_profiled":1310},"omim":[{"mim_id":"608348","title":"BRANCHED-CHAIN KETO ACID DEHYDROGENASE E1, ALPHA POLYPEPTIDE; BCKDHA","url":"https://www.omim.org/entry/608348"},{"mim_id":"607008","title":"ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN; ACADM","url":"https://www.omim.org/entry/607008"},{"mim_id":"600141","title":"HEAT-SHOCK 10-KD PROTEIN; HSPE1","url":"https://www.omim.org/entry/600141"},{"mim_id":"118190","title":"HEAT-SHOCK 60-KD PROTEIN 1; HSPD1","url":"https://www.omim.org/entry/118190"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":1080.8}],"url":"https://www.proteinatlas.org/search/HSPE1"},"hgnc":{"alias_symbol":["CPN10","GroES","HSP10","EPF"],"prev_symbol":[]},"alphafold":{"accession":"P61604","domains":[{"cath_id":"2.30.33.40","chopping":"15-21_34-96","consensus_level":"high","plddt":92.0194,"start":15,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61604","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61604-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61604-F1-predicted_aligned_error_v6.png","plddt_mean":87.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSPE1","jax_strain_url":"https://www.jax.org/strain/search?query=HSPE1"},"sequence":{"accession":"P61604","fasta_url":"https://rest.uniprot.org/uniprotkb/P61604.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61604/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61604"}},"corpus_meta":[{"pmid":"9572938","id":"PMC_9572938","title":"Chaperone coexpression plasmids: differential and synergistic roles of DnaK-DnaJ-GrpE and GroEL-GroES in assisting folding of an allergen of Japanese cedar pollen, Cryj2, in Escherichia coli.","date":"1998","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9572938","citation_count":347,"is_preprint":false},{"pmid":"3017973","id":"PMC_3017973","title":"Purification and properties of the groES morphogenetic protein of Escherichia coli.","date":"1986","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3017973","citation_count":303,"is_preprint":false},{"pmid":"26422689","id":"PMC_26422689","title":"The GroEL-GroES Chaperonin Machine: A Nano-Cage for Protein Folding.","date":"2015","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26422689","citation_count":300,"is_preprint":false},{"pmid":"7901770","id":"PMC_7901770","title":"The reaction cycle of GroEL and GroES in chaperonin-assisted protein 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22977243","citation_count":18,"is_preprint":false},{"pmid":"28271487","id":"PMC_28271487","title":"GroEL and the GroEL-GroES Complex.","date":"2017","source":"Sub-cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28271487","citation_count":17,"is_preprint":false},{"pmid":"15862128","id":"PMC_15862128","title":"Stage-specific expression of the mitochondrial co-chaperonin of Leishmania donovani, CPN10.","date":"2005","source":"Kinetoplastid biology and disease","url":"https://pubmed.ncbi.nlm.nih.gov/15862128","citation_count":17,"is_preprint":false},{"pmid":"26858694","id":"PMC_26858694","title":"Chaperonin GroEL/GroES Over-Expression Promotes Aminoglycoside Resistance and Reduces Drug Susceptibilities in Escherichia coli Following Exposure to Sublethal Aminoglycoside Doses.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26858694","citation_count":17,"is_preprint":false},{"pmid":"26562693","id":"PMC_26562693","title":"Overproduction of the Escherichia coli Chaperones GroEL-GroES in Rhodococcus ruber Improves the Activity and Stability of Cell Catalysts Harboring a Nitrile Hydratase.","date":"2016","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26562693","citation_count":17,"is_preprint":false},{"pmid":"36818283","id":"PMC_36818283","title":"Role of human HSPE1 for OPA1 processing independent of HSPD1.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36818283","citation_count":16,"is_preprint":false},{"pmid":"20835829","id":"PMC_20835829","title":"Changes in ffh, uvrA, groES and dnaK mRNA abundance as a function of acid-adaptation and growth phase in Bifidobacterium longum BBMN68 isolated from healthy centenarians.","date":"2010","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20835829","citation_count":16,"is_preprint":false},{"pmid":"26429916","id":"PMC_26429916","title":"Interaction of Heat Shock Protein Cpn10 with the Cyclin E/Cdk2 Substrate Nuclear Protein Ataxia-Telangiectasia (NPAT) Is Involved in Regulating Histone Transcription.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26429916","citation_count":15,"is_preprint":false},{"pmid":"24247249","id":"PMC_24247249","title":"Chaperones GroEL/GroES accelerate the refolding of a multidomain protein through modulating on-pathway intermediates.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24247249","citation_count":15,"is_preprint":false},{"pmid":"9856102","id":"PMC_9856102","title":"Chaperone protein GrpE and the GroEL/GroES complex promote the correct folding of tobacco mosaic virus coat protein for ribonucleocapsid assembly in vivo.","date":"1998","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/9856102","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48779,"output_tokens":5093,"usd":0.111366,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13444,"output_tokens":4538,"usd":0.090335,"stage2_stop_reason":"end_turn"},"total_usd":0.201701,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Mitochondrial cpn10 (HSP10/HSPE1 homologue) was identified in beef and rat liver mitochondria as functionally equivalent to E. coli GroES; it forms a stable complex with bacterial cpn60 in the presence of Mg·ATP, competes with bacterial cpn10 for a common saturable site on cpn60, and virtually abolishes the 'uncoupled ATPase' activity of cpn60 upon complex formation, thereby facilitating ATP/K+-dependent discharge of unfolded substrate protein from cpn60.\",\n      \"method\": \"In vitro reconstitution of RuBisCO refolding, ATPase inhibition assay, stable complex formation with Mg·ATP, competition binding\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro reconstitution assays (refolding, ATPase inhibition, complex formation, competition) establishing functional equivalence and direct physical interaction\",\n      \"pmids\": [\"1977163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast mitochondrial Hsp10 (HSPE1 orthologue) is an essential component of the mitochondrial protein-folding apparatus; temperature-sensitive hsp10 mutants fail to fold and assemble proteins imported into the matrix compartment and are also required for sorting of the Rieske Fe/S protein through the matrix. The temperature-sensitive mutations map to the mobile loop region (residues 25–40) and result in reduced binding affinity for Hsp60 at the non-permissive temperature.\",\n      \"method\": \"Yeast genetics (temperature-sensitive lethal mutants), import/folding assays, biochemical fractionation, site mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with defined folding and sorting phenotypes, plus domain-level mutagenesis identifying the mobile loop as critical for Hsp60 binding\",\n      \"pmids\": [\"7913473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast mitochondrial in vivo substrates fall into three groups: (i) proteins requiring both Hsp60 and Hsp10 for folding; (ii) proteins that fail to fold without Hsp60 but are unaffected by Hsp10 inactivation; (iii) newly imported Hsp60 itself, which is more severely affected by Hsp10 inactivation than by loss of pre-existing Hsp60. This demonstrates that Hsp10 and Hsp60 do not always act as a single functional unit in vivo.\",\n      \"method\": \"Novel in vivo substrate screen in S. cerevisiae using temperature-sensitive hsp60 and hsp10 mutants, molecular weight determination of ~15–90 kDa substrates\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic screen with two independent conditional mutants and multiple substrates, revealing differential chaperonin requirements\",\n      \"pmids\": [\"9774331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Overexpression of HSP60 and HSP10 (individually or in combination) in rat neonatal cardiac myocytes protected against simulated ischemia/reoxygenation-induced apoptosis, reducing mitochondrial cytochrome c release, caspase-3 activation, and maintaining ATP levels through preserved electron transport chain complex III and IV activities.\",\n      \"method\": \"Adenoviral overexpression in primary cardiomyocytes, enzyme release/DNA fragmentation/caspase-3 assays, mitochondrial ETC activity measurements, ATP quantification\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression with multiple functional readouts (apoptosis, ETC activity, ATP), single lab\",\n      \"pmids\": [\"11282911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of Hsp10 or Hsp60 in cardiomyocytes suppressed doxorubicin-induced apoptosis by differentially modulating Bcl-2 family members; both proteins increased Bcl-xl and Bcl-2 and reduced Bax at the post-translational level by inhibiting ubiquitination of Bcl-xl (shown to be cycloheximide-insensitive and mRNA-independent). Hsp60 additionally interacted with Bcl-xl and Bax by co-immunoprecipitation in vivo.\",\n      \"method\": \"Adenoviral overexpression in primary cardiomyocytes, co-immunoprecipitation, cycloheximide chase, ubiquitination assay, antisense Hsp60 knockdown\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP for Hsp60-Bcl-xl/Bax interaction, multiple functional readouts, single lab; Hsp10-specific interaction with Bcl family not shown by co-IP\",\n      \"pmids\": [\"12967636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hsp10 and Hsp60 overexpression in cardiomyocytes increased IGF-1 receptor (IGF-1R) abundance and IGF-1-stimulated autophosphorylation by suppressing polyubiquitination of IGF-1R, a post-translational mechanism independent of protein synthesis or mRNA upregulation. Conversely, antisense Hsp60 knockdown decreased IGF-1R abundance and attenuated IGF-1R signaling and pro-survival actions.\",\n      \"method\": \"Adenoviral overexpression/antisense knockdown in neonatal cardiomyocytes, ubiquitination assay, cycloheximide chase, phosphorylation assays for IGF-1R and downstream kinases\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (ubiquitination assay, cycloheximide chase, signaling readouts), single lab; Hsp10 role inferred from overexpression without direct binding demonstration\",\n      \"pmids\": [\"12970367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hsp10 protection of cardiac myocytes against simulated ischemia/reoxygenation requires its mobile loop (a P34H mobile-loop mutant incapable of co-refolding malate dehydrogenase with Hsp60 potentiated cell death). Protection involves preservation of mitochondrial complex I and II function and requires inactivation of the Ras GTPase pathway; Hsp10 overexpression inactivated Raf, ERK, and p90RSK, and constitutively active Ras abolished Hsp10-mediated protection.\",\n      \"method\": \"Adenoviral overexpression of wild-type and P34H mutant Hsp10, ETC complex activity assays, Ras pathway inhibitor studies, constitutively active Ras co-expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-function mutagenesis (mobile loop mutant) combined with pathway epistasis (Ras inhibitor, constitutively active Ras), single lab\",\n      \"pmids\": [\"15059967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The human HSP60 (HSPD1) and HSP10 (HSPE1) genes are arranged head-to-head on chromosome 2q33.1, separated by a bidirectional promoter (~17 kb total); luciferase reporter assays demonstrated bidirectional promoter activity that increases ~12-fold upon heat shock in both directions, with a STAT3-binding site identified as a regulatory element.\",\n      \"method\": \"Genomic sequencing, radiation hybrid mapping, luciferase reporter assay, heat-shock induction\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional promoter assay with deletion/mutation analysis, single lab\",\n      \"pmids\": [\"12483302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NO (from iNOS) downregulates HSP60 and HSP10 expression in the postischemic brain by suppressing STAT3 binding to its recognition site in the bidirectional promoter; reporter gene analysis with deletion and mutation studies identified the STAT3 site as responsible for LPS/IFN-γ-induced upregulation and for NO-mediated downregulation.\",\n      \"method\": \"Middle cerebral artery occlusion mouse model, iNOS inhibitor (aminoguanidine), C6 astroglioma cell LPS/IFN-γ treatment, iNOS inhibitor NMMA, luciferase reporter with promoter deletion/mutation\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter gene with deletion/mutation analysis identifying STAT3 site, confirmed in vivo and in vitro, single lab\",\n      \"pmids\": [\"17348040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mitochondrial Hsp70 (mtHsp70) associates with Hsp10 independently of Hsp60; the mtHsp70–Hsp10 complex binds to unassembled Hsp60 precursor and promotes its assembly into mature heptameric Hsp60 complexes. This places HSPE1 as a co-factor for Hsp60 biogenesis in addition to its folding co-chaperonin role.\",\n      \"method\": \"Comprehensive interaction study by MS-based co-immunoprecipitation in yeast mitochondria, including controls separating Hsp70–Hsp10 interaction from Hsp60\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome with multiple co-IP controls establishing independent Hsp10–Hsp70 interaction, single lab\",\n      \"pmids\": [\"25792736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A de novo missense mutation in HSPE1 (c.217C>T, p.Leu73Phe) causes near-complete loss of the mutant HSP10 protein in patient fibroblasts (detected by mass spectrometry), resulting in an ~2-fold decrease in the HSP10:HSP60 ratio, ~80% reduction of SOD2 protein (a known HSP60/HSP10 substrate) without change in SOD2 mRNA, and ~2-fold increase in mitochondrial superoxide levels. In vitro, the purified mutant protein had profoundly impaired thermal stability, refolding propensity, and protease resistance.\",\n      \"method\": \"Clinical exome sequencing, mass spectrometry of patient fibroblasts, in vitro purification and functional characterization of mutant HSP10, mRNA/protein quantification, mitochondrial superoxide measurement\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — combines in vitro biochemical characterization of mutant protein with ex vivo patient fibroblast proteomics and functional consequences, single lab, case study\",\n      \"pmids\": [\"27774450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cross-linking immunoprecipitation/MS survey of the human mitochondrial HSP60/HSP10 chaperonin in HEK293 cells identified 323 interacting proteins; ~50% of annotated mitochondrial matrix proteins interact with HSP60/HSP10, covering the respiratory chain, mitochondrial protein synthesis apparatus, and protein quality control. Nineteen abundant matrix proteins occupy >60% of HSP60/HSP10 chaperonin capacity.\",\n      \"method\": \"Metabolic labeling of HEK293 cells, chemical cross-linking, HSP60 immunoprecipitation, quantitative mass spectrometry\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic MS interactome with cross-linking and quantitative labeling, single lab; broad interactome survey rather than individual mechanistic validation\",\n      \"pmids\": [\"32060690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HSPE1/Cpn10 (a pool) localizes to the nucleus where it co-localizes with NPAT foci during G1 and S phases. Cpn10 interacts with NPAT (a Cyclin E/CDK2 substrate that regulates histone transcription) via a conserved DLFD motif; knockdown of Cpn10 disrupts NPAT focus formation and reduces histone gene transcription and S-phase progression, while overexpression promotes histone transcription.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, gain- and loss-of-function (siRNA knockdown, overexpression), motif mutagenesis (DLFD), histone mRNA quantification, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutational dissection of DLFD motif, and multiple functional readouts in a single study; single lab\",\n      \"pmids\": [\"26429916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human HSP60 possesses GTPase activity; in the presence of GTP versus ATP, the HSP60-HSP10 complex shows different allosteric properties, complex formation characteristics, and protein folding activity, indicating that nucleotide identity modulates the functional mechanism of the HSP60-HSP10 complex.\",\n      \"method\": \"In vitro GTPase and ATPase activity assays, protein folding assays with HSP60/HSP10 complex\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro biochemical assay, limited mechanistic detail available from abstract alone\",\n      \"pmids\": [\"29208924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Depletion of HSPE1 (but not HSPD1) in HEK293T cells causes mitochondrial fragmentation through proteolytic inactivation of OPA1 mediated by the stress-activated metalloprotease OMA1, revealing a chaperonin-activity-independent role of HSPE1 in controlling mitochondrial morphology and fusion.\",\n      \"method\": \"siRNA knockdown of HSPD1 and HSPE1 in HEK293T cells, mitochondrial morphology imaging, OPA1 processing assay, OMA1 activation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic separation of HSPE1 vs. HSPD1 knockdown with specific mechanistic readout (OMA1/OPA1 cleavage), single lab, two orthogonal phenotypic/biochemical approaches\",\n      \"pmids\": [\"36818283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Glutamine activates SIRT4 (by increasing NAD+ and SIRT4 protein levels), which deacetylates HSP60 to promote assembly of the HSP60–HSP10 complex in mitochondria; restored complex activity maintains electron transport chain complex II and III function, ATP generation, and reduces reactive oxygen species in hepatocytes under burn sepsis conditions.\",\n      \"method\": \"In vitro and in vivo burn-sepsis model, NAD+ measurement, SIRT4 protein quantification, HSP60 acetylation assay, ETC complex activity assays, ATP measurement, ROS quantification\",\n      \"journal\": \"Redox report\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-step mechanistic pathway (Gln→SIRT4→HSP60 deacetylation→HSP60-HSP10 assembly→ETC function) with multiple orthogonal assays, single lab\",\n      \"pmids\": [\"38329114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GroES (the bacterial HSPE1 homologue) has no affinity for nucleotides: photolabeling of GroES with 8-azido-ATP was found to be non-specific (other non-nucleotide-binding proteins were also labeled), and rigorous isothermal calorimetry and equilibrium binding assays detected no interaction between GroES and nucleotides.\",\n      \"method\": \"Isothermal calorimetry, equilibrium binding, 8-azido-ATP photolabeling with controls\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — negative result established by two orthogonal rigorous physical methods (ITC + equilibrium binding) correcting a prior claim; mechanistically informative negative finding\",\n      \"pmids\": [\"7867782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HSP10 is detected in the sera, ascites, and conditioned media of ovarian cancer patients but not controls; immunoprecipitation removal of HSP10 from patient sera diminished the ability to suppress T-cell CD3-zeta expression, while the immunoprecipitate alone suppressed CD3-zeta, identifying secreted HSP10 as a direct suppressor of T-cell activation.\",\n      \"method\": \"Western immunoblotting of sera/ascites/conditioned media, immunoprecipitation depletion/reconstitution bioassay using Jurkat cells, CD3-zeta expression quantification\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited patient numbers (n=10), bioassay with immunodepletion; functional mechanism of CD3-zeta suppression not defined beyond HSP10 presence\",\n      \"pmids\": [\"16386781\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPE1 (HSP10) encodes the mitochondrial co-chaperonin that forms a functional complex with HSP60 (HSPD1) to mediate ATP-dependent protein folding in the mitochondrial matrix via its mobile loop, which binds HSP60 and gates substrate release; independently of this canonical activity, HSPE1 controls mitochondrial morphology by preventing OMA1-mediated OPA1 cleavage, participates in Hsp60 ring assembly together with mtHsp70, modulates post-translational stability of Bcl-2 family members and IGF-1R via ubiquitination suppression in cardiomyocytes, and—in a non-mitochondrial nuclear pool—interacts with NPAT through a conserved DLFD motif to regulate histone gene transcription and S-phase progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HSPE1 (HSP10/cpn10) is the mitochondrial co-chaperonin that partners with HSP60 (HSPD1) to drive ATP-dependent folding of matrix proteins, the functional equivalent of bacterial GroES [#0]. It binds HSP60 in a Mg·ATP-dependent manner, abolishing the uncoupled ATPase activity of HSP60 to gate discharge of unfolded substrate [#0], and this interaction depends on its mobile loop (residues 25–40), where temperature-sensitive mutations reduce HSP60 affinity and abolish folding and matrix sorting in vivo [#1]; the same mobile loop is required for HSP10's protective and co-refolding activity, as a P34H mutant cannot co-refold substrate with HSP60 [#6]. Genetic dissection shows HSP10 and HSP60 do not always act as one unit, with distinct in vivo substrate classes and a specific requirement for HSP10 in folding newly imported HSP60 itself [#2]. Beyond folding, HSPE1 acts as a co-factor for HSP60 biogenesis: an mtHsp70–HSP10 complex, formed independently of HSP60, binds unassembled HSP60 precursor and promotes its assembly into mature heptamers [#9], and this assembly is further tuned by SIRT4-mediated deacetylation of HSP60 to maintain electron transport chain function and limit ROS [#15]. The HSP60/HSP10 chaperonin engages roughly half of the annotated matrix proteome, including the respiratory chain, mitochondrial translation machinery, and quality-control factors [#11], and is human HSP60's catalytic partner whose folding output is modulated by nucleotide identity [#13]. HSPE1 also performs chaperonin-independent functions: its depletion (but not that of HSPD1) triggers OMA1-mediated OPA1 cleavage and mitochondrial fragmentation, linking it to mitochondrial morphology and fusion [#14], and a nuclear pool interacts with NPAT through a conserved DLFD motif to organize NPAT foci and drive histone gene transcription and S-phase progression [#12]. A de novo p.Leu73Phe mutation that destabilizes HSP10 lowers the HSP10:HSP60 ratio, depletes the substrate SOD2, and raises mitochondrial superoxide, establishing HSPE1 as the cause of a human mitochondrial disorder [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that mammalian HSP10 is the functional co-chaperonin of HSP60, defining the core biochemical mechanism of ATP-dependent substrate discharge.\",\n      \"evidence\": \"In vitro RuBisCO refolding, ATPase inhibition, Mg·ATP-dependent complex formation, and competition binding with bacterial cpn60\",\n      \"pmids\": [\"1977163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which residues mediate the HSP60 contact\", \"Performed with bacterial cpn60 rather than mammalian HSP60\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed HSP10 is essential for matrix protein folding and sorting in vivo and pinpointed the mobile loop as the HSP60-binding determinant.\",\n      \"evidence\": \"Temperature-sensitive hsp10 lethal mutants in yeast with import/folding and Rieske Fe/S sorting assays and site mapping to residues 25-40\",\n      \"pmids\": [\"7913473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not enumerate the full set of dependent substrates\", \"Structural basis of mobile-loop/HSP60 contact not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Revealed that HSP10 and HSP60 are not obligately coupled in vivo, with distinct substrate dependencies including a special role in folding newly imported HSP60.\",\n      \"evidence\": \"In vivo substrate screen using conditional hsp60 and hsp10 mutants in S. cerevisiae\",\n      \"pmids\": [\"9774331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for HSP10-independent HSP60 folding not defined\", \"Substrate identities only resolved by molecular weight\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected HSP10/HSP60 chaperonin function to cytoprotection, showing overexpression preserves respiratory function and blocks ischemic apoptosis.\",\n      \"evidence\": \"Adenoviral overexpression in rat cardiomyocytes with apoptosis, ETC complex III/IV activity, and ATP readouts\",\n      \"pmids\": [\"11282911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Could not separate HSP10-specific from HSP60 contributions\", \"Mechanism of cytochrome c retention not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified post-translational, ubiquitination-dependent control of apoptotic and survival factors as a downstream consequence of HSP10/HSP60 expression.\",\n      \"evidence\": \"Adenoviral overexpression/antisense knockdown in cardiomyocytes with co-IP, cycloheximide chase, and ubiquitination assays for Bcl-2 family and IGF-1R\",\n      \"pmids\": [\"12967636\", \"12970367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HSP10-specific direct binding to Bcl-xl/Bax/IGF-1R not demonstrated\", \"Identity of the responsible ubiquitin ligase or DUB unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that HSP10 cytoprotection requires its mobile loop and an intact Ras pathway inactivation step, tying folding capacity to a signaling outcome.\",\n      \"evidence\": \"Adenoviral wild-type vs P34H mobile-loop mutant Hsp10 with ETC assays and Ras pathway epistasis (inhibitor and constitutively active Ras)\",\n      \"pmids\": [\"15059967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking chaperonin activity to Ras/Raf/ERK inactivation not defined\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the genomic and transcriptional control of HSPE1, showing it shares a heat-inducible bidirectional promoter with HSPD1 regulated by a STAT3 site.\",\n      \"evidence\": \"Genomic mapping and luciferase reporter assays with heat-shock induction at the 2q33.1 locus\",\n      \"pmids\": [\"12483302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcription factors at the promoter not characterized\", \"Reporter-based, not endogenous chromatin context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended transcriptional control to a physiological setting, showing NO/iNOS downregulates HSPE1 via the STAT3 promoter element after ischemia.\",\n      \"evidence\": \"MCAO mouse model with iNOS inhibitors and C6 astroglioma reporter assays with promoter deletion/mutation\",\n      \"pmids\": [\"17348040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of HSPE1 loss in postischemic brain not measured\", \"Mechanism of NO action on STAT3 not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered a non-mitochondrial nuclear role for HSPE1 in histone gene transcription and S-phase progression through NPAT binding.\",\n      \"evidence\": \"Reciprocal co-IP, confocal co-localization, DLFD motif mutagenesis, knockdown/overexpression, histone mRNA and cell cycle analysis\",\n      \"pmids\": [\"26429916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPE1 partitions between mitochondria and nucleus unknown\", \"Whether nuclear function requires chaperonin activity unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Recast HSPE1 as a co-factor for HSP60 biogenesis, forming an HSP60-independent complex with mtHsp70 that assembles HSP60 heptamers.\",\n      \"evidence\": \"MS-based co-IP interactome in yeast mitochondria with controls separating Hsp70-Hsp10 from Hsp60\",\n      \"pmids\": [\"25792736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of the mtHsp70-HSP10 complex not resolved\", \"Whether this applies in human mitochondria not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided human disease causation, linking a destabilizing HSPE1 mutation to substrate (SOD2) loss and oxidative stress.\",\n      \"evidence\": \"Exome sequencing, patient fibroblast mass spectrometry, in vitro mutant characterization, and mitochondrial superoxide measurement\",\n      \"pmids\": [\"27774450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case study\", \"Full clinical spectrum and additional affected substrates not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the global substrate landscape of the HSP60/HSP10 chaperonin in human cells, defining its proteostatic scope.\",\n      \"evidence\": \"Cross-linking HSP60 immunoprecipitation with quantitative mass spectrometry in HEK293 cells\",\n      \"pmids\": [\"32060690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not distinguish obligate clients from transient interactors\", \"HSP10-specific contribution to each interaction not parsed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a chaperonin-independent function of HSPE1 in mitochondrial morphology by preventing OMA1-mediated OPA1 cleavage.\",\n      \"evidence\": \"Selective siRNA knockdown of HSPE1 vs HSPD1 in HEK293T with morphology imaging and OPA1/OMA1 processing assays\",\n      \"pmids\": [\"36818283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HSPE1 loss activates OMA1 unknown\", \"Whether mobile loop or chaperonin contacts are involved not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed an upstream regulatory input controlling HSP60-HSP10 assembly via SIRT4-mediated HSP60 deacetylation to sustain respiration.\",\n      \"evidence\": \"Burn-sepsis in vitro/in vivo model with NAD+, SIRT4, HSP60 acetylation, ETC complex II/III activity, ATP, and ROS measurements\",\n      \"pmids\": [\"38329114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HSP60 acetylation sites controlling HSP10 binding not mapped\", \"Single disease-model context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HSPE1 is partitioned and regulated across its mitochondrial folding, mitochondrial morphology, nuclear histone-transcription, and secreted immunomodulatory roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating mobile-loop folding with non-canonical functions\", \"Mechanism of nuclear/extracellular localization undefined\", \"Secreted HSP10 mechanism of CD3-zeta suppression not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 9, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"HSP60-HSP10 (cpn60/cpn10) chaperonin\", \"mtHsp70-Hsp10 complex\"],\n    \"partners\": [\"HSPD1\", \"HSPA9\", \"NPAT\", \"OMA1\", \"OPA1\", \"SIRT4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}