HSP60

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference is well supported. HSP60 is a group I chaperonin whose primary function is protein folding in the mitochondrial matrix. PMID:2645524 showed HSP60 is essential for assembly of imported proteins, and PMID:1978929 demonstrated it is required for its own de novo folding. Supporting Evidence: PMID:2645524 Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. PMID:1978929 Hsp60 monomers form a complex arranged as two stacked 7-mer rings. This 14-mer complex binds unfolded proteins at its surface, then seems to catalyse their folding in an ATP-dependent process. file:yeast/HSP60/HSP60-deep-research-falcon.md In yeast specifically, Hsp60 forms a 14-subunit double-ring (two heptameric rings), creating a cavity that can accommodate client proteins up to ~50 kDa, and imported precursor proteins transiently associate with Hsp60 as incompletely folded intermediates before ATP-dependent folding/release.
GO:0007005 mitochondrion organization	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference is supported by experimental evidence. HSP60 is essential for mitochondrial biogenesis; loss-of-function mutants show defects in mitochondrial protein assembly and mtDNA maintenance (PMID:2645524, PMID:14597775). Supporting Evidence: PMID:2645524 Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. PMID:14597775 A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. file:yeast/HSP60/HSP60-deep-research-falcon.md HSP60 is essential for viability: deletion/null mutants are inviable due to severe mitochondrial folding defects.
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: HSP60 is primarily a soluble matrix protein. There is some association with the inner membrane, possibly through its role in the TIM23-PAM import machinery, but the primary active location is the mitochondrial matrix. This IBA annotation is acceptable as HSP60 may be active at the inner membrane during protein import. Reason: HSP60 is primarily a matrix protein; inner membrane association is secondary to its import-related functions.
GO:0005759 mitochondrial matrix	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference consistent with UniProt annotation (PMID:11502169) and experimental localization data. The mitochondrial matrix is the primary location where HSP60 functions. Supporting Evidence: PMID:11502169 Yeast mitochondrial dehydrogenases are associated in a supramolecular complex. file:yeast/HSP60/HSP60-deep-research-falcon.md Yeast Hsp60 is produced as a mitochondrial precursor with an N-terminal matrix-targeting presequence, cleaved by MPP after residue 21, consistent with mitochondrial import and processing to a mature matrix protein.
GO:0034514 mitochondrial unfolded protein response	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference. HSP60 expression is induced by mitochondrial stress and heat shock. As a major mitochondrial chaperonin, it is a key effector of the mitochondrial unfolded protein response. This is a secondary/responsive function rather than core enzymatic activity. Reason: This is a stress response pathway annotation; the core function is ATP-dependent protein folding.
GO:0045041 protein import into mitochondrial intermembrane space	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference supported by experimental evidence from PMID:1347713, which demonstrated that HSP60 couples protein import into the matrix with export to the intermembrane space. Reason: This is a secondary function of HSP60 related to its role in the TIM23/PAM import pathway; the core function is protein folding in the matrix. Supporting Evidence: PMID:1347713 Antifolding activity of hsp60 couples protein import into the mitochondrial matrix with export to the intermembrane space.
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference supported by direct experimental evidence. PMID:9256426 demonstrated physical interaction between HSP60 and HSP10 (co-chaperonin) with measured binding constants (Kd 0.9 nM in ADP). Supporting Evidence: PMID:9256426 In the presence of ADP, one molecule of hsp10 binds to hsp60 with an apparent Kd of 0.9 nM and a second molecule of hsp10 binds with a Kd of 24 nM. file:yeast/HSP60/HSP60-deep-research-falcon.md the co-chaperonin Hsp10 (GroES-like) caps the cavity (“lid”), enabling an encapsulated folding environment; ATP hydrolysis and nucleotide exchange govern release/reset.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	MODIFY	Summary: Overly general IEA annotation based on UniProt keyword. HSP60 specifically binds ATP; the more specific term GO:0005524 (ATP binding) is already annotated. Reason: Too general; ATP binding is the correct specific term. Proposed replacements: ATP binding
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation consistent with HSP60 being an ATPase chaperonin. HSP60 binds and hydrolyzes ATP as part of its folding cycle. Supported by direct assay in PMID:7902576 and PMID:9256426. Supporting Evidence: PMID:7902576 Identification and functional analysis of chaperonin 10, the groES homolog from yeast mitochondria. PMID:9256426 Hsp10 inhibits the ATPase activity of hsp60 by about 40%.
GO:0005737 cytoplasm	IEA GO_REF:0000117	REMOVE	Summary: ARBA machine learning annotation. HSP60 is synthesized in the cytoplasm as a precursor but its functional location is the mitochondrial matrix. This annotation is misleading as it does not reflect the active location of the protein. Falcon notes that a small extra-mitochondrial pool (~15-20% cytoplasmic) has been reported for HSP60 in higher eukaryotes, but explicitly flags this distribution as "not yeast-specific", so it does not justify a yeast cytoplasm annotation. Reason: HSP60 is a mitochondrial matrix protein. Cytoplasmic presence is only transient during import; the reported cytoplasmic pool is from mammalian studies, not yeast. Supporting Evidence: file:yeast/HSP60/HSP60-deep-research-falcon.md In broader eukaryotic contexts, HSP60 is predominantly mitochondrial and can also be detected in extra-mitochondrial compartments; one 2024 review summarizes a distribution of ~80–85% mitochondrial and ~15–20% cytoplasmic for HSP60 (not yeast-specific).
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation based on UniProt subcellular location. Consistent with IBA and experimental evidence. Redundant with IBA annotation but correct.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based IEA annotation. Redundant with IBA and IMP evidence for the same term, but correct.
GO:0042026 protein refolding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based IEA annotation. Consistent with experimental evidence from PMID:1359644 and PMID:9256426 showing HSP60 mediates ATP-dependent refolding of denatured proteins. Supporting Evidence: PMID:1359644 Hsp60 bound to DHFR in the course of thermal denaturation, preventing its aggregation, and mediated its adenosine triphosphate-dependent refolding at increased temperatures. PMID:9256426 In the presence of ATP, the purified yeast chaperonins mediate the refolding of mitochondrial malate dehydrogenase.
GO:0051082 unfolded protein binding	IEA GO_REF:0000117	MODIFY	Summary: GO:0051082 is now formally obsolete. HSP60 is an ATP-dependent group I chaperonin (foldase) that actively folds proteins, not merely a passive binding protein. The correct term is GO:0140662 (ATP-dependent protein folding chaperone). Reason: GO:0051082 is now formally obsolete. HSP60 is a bona fide ATP-dependent foldase chaperonin, not a passive unfolded protein binder. Proposed replacements: ATP-dependent protein folding chaperone
GO:0140662 ATP-dependent protein folding chaperone	IEA GO_REF:0000002	ACCEPT	Summary: This is the correct and most informative molecular function term for HSP60. It is a group I chaperonin that uses ATP hydrolysis to fold substrate proteins within its central cavity. Supported by PMID:7902576 (ATPase activity), PMID:9256426 (ATP-dependent refolding of malate dehydrogenase), and PMID:1359644 (ATP-dependent refolding of DHFR). Reason: This is the primary molecular function of HSP60 and the correct replacement for GO:0051082. Supporting Evidence: PMID:9256426 In the presence of ATP, the purified yeast chaperonins mediate the refolding of mitochondrial malate dehydrogenase. PMID:1359644 Hsp60 bound to DHFR in the course of thermal denaturation, preventing its aggregation, and mediated its adenosine triphosphate-dependent refolding at increased temperatures. file:yeast/HSP60/HSP60-deep-research-falcon.md ATP-dependent protein folding chaperonin for mitochondrial matrix proteins, particularly those imported into mitochondria as unfolded precursors. file:yeast/HSP60/HSP60-deep-research-falcon.md Hsp60 does not catalyze a chemical transformation of a small molecule substrate; rather, it catalyzes conformational maturation of polypeptides by providing a protected folding environment and coordinating binding/release with ATP hydrolysis and Hsp10 capping.
GO:0005515 protein binding	IPI PMID:11805837 Systematic identification of protein complexes in Saccharomy...	MARK AS OVER ANNOTATED	Summary: High-throughput mass spectrometry identification of protein complexes. Protein binding is uninformative for a chaperonin that interacts with many client proteins. The binding reflects chaperone-client interactions. Reason: Protein binding is uninformative for a chaperonin; its binding to clients is part of its ATP-dependent protein folding chaperone activity.
GO:0005515 protein binding	IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine...	MARK AS OVER ANNOTATED	Summary: Same rationale as above. Protein binding is uninformative for a chaperonin. Reason: Protein binding is uninformative for a chaperonin.
GO:0005515 protein binding	IPI PMID:16554755 Global landscape of protein complexes in the yeast Saccharom...	MARK AS OVER ANNOTATED	Summary: Same rationale as above. Protein binding is uninformative for a chaperonin. Reason: Protein binding is uninformative for a chaperonin.
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	MARK AS OVER ANNOTATED	Summary: Chaperone-protein interaction atlas. Protein binding is uninformative for a chaperonin. Reason: Protein binding is uninformative for a chaperonin.
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MARK AS OVER ANNOTATED	Summary: Same rationale as above. Reason: Protein binding is uninformative for a chaperonin.
GO:0042645 mitochondrial nucleoid	IDA PMID:14597775 A function for the mitochondrial chaperonin Hsp60 in the str...	ACCEPT	Summary: Direct experimental evidence showing HSP60 localizes to mitochondrial nucleoids. PMID:14597775 demonstrated a function for HSP60 in the structure and transmission of mtDNA nucleoids. Supporting Evidence: PMID:14597775 A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae.
GO:0051082 unfolded protein binding	IMP PMID:1359644 Prevention of protein denaturation under heat stress by the ...	MODIFY	Summary: PMID:1359644 showed that HSP60 forms complexes with polypeptides in organelles exposed to heat stress and mediates ATP-dependent refolding. This is active chaperonin-mediated folding, not passive unfolded protein binding. The correct term is GO:0140662 (ATP-dependent protein folding chaperone). Reason: GO:0051082 is now formally obsolete. The experiment demonstrates ATP-dependent chaperonin folding activity, which is GO:0140662. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:1359644 Hsp60 bound to DHFR in the course of thermal denaturation, preventing its aggregation, and mediated its adenosine triphosphate-dependent refolding at increased temperatures.
GO:0005739 mitochondrion	HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph...	KEEP AS NON CORE	Summary: High-throughput proteomics of mitochondria. Consistent with known localization. Less specific than mitochondrial matrix but correct. Reason: Correct but less specific than mitochondrial matrix.
GO:0005739 mitochondrion	HDA PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria.	KEEP AS NON CORE	Summary: Mitochondrial proteomics. Consistent with known localization. Reason: Correct but less specific than mitochondrial matrix.
GO:0005739 mitochondrion	HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen...	KEEP AS NON CORE	Summary: Mitochondrial proteomics. Consistent with known localization. Reason: Correct but less specific than mitochondrial matrix.
GO:0003688 DNA replication origin binding	IDA PMID:10869431 In organello formaldehyde crosslinking of proteins to mtDNA:...	KEEP AS NON CORE	Summary: PMID:10869431 used in organello formaldehyde crosslinking to identify HSP60 as a bifunctional protein that binds mtDNA replication origins. This is a secondary moonlighting function related to mtDNA maintenance, not the core protein folding function. Reason: This is a moonlighting function related to mtDNA nucleoid maintenance, distinct from the core chaperonin folding activity. Supporting Evidence: PMID:10869431 In organello formaldehyde crosslinking of proteins to mtDNA: identification of bifunctional proteins.
GO:0003697 single-stranded DNA binding	IDA PMID:10869431 In organello formaldehyde crosslinking of proteins to mtDNA:...	KEEP AS NON CORE	Summary: Same paper as DNA replication origin binding. HSP60 was shown to bind ssDNA in the context of mtDNA nucleoid maintenance. This is a moonlighting function. Reason: Moonlighting function related to mtDNA maintenance; not the core chaperonin activity.
GO:0005739 mitochondrion	IDA PMID:11502169 Yeast mitochondrial dehydrogenases are associated in a supra...	KEEP AS NON CORE	Summary: Direct experimental evidence of mitochondrial localization from protein sequencing study. Reason: Correct but less specific than mitochondrial matrix.
GO:0005739 mitochondrion	IDA PMID:8097278 Loss of mitochondrial hsp60 function: nonequivalent effects ...	KEEP AS NON CORE	Summary: Direct experimental evidence of mitochondrial localization. PMID:8097278 studied loss of mitochondrial hsp60 function. Reason: Correct but less specific than mitochondrial matrix.
GO:0006458 'de novo' protein folding	IMP PMID:1978929 The mitochondrial chaperonin hsp60 is required for its own a...	ACCEPT	Summary: PMID:1978929 demonstrated that HSP60 is required for its own assembly - newly imported HSP60 monomers require functional pre-existing HSP60 complex to fold and assemble into the tetradecamer. This is direct evidence for de novo protein folding activity. Supporting Evidence: PMID:1978929 Functional pre-existing hsp60 complex is required in order to form new, assembled, 14-mer. Subunits imported in vitro are assembled with a surprisingly fast half-time of 5-10 min, indicative of a catalysed reaction.
GO:0016887 ATP hydrolysis activity	IDA PMID:7902576 Identification and functional analysis of chaperonin 10, the...	ACCEPT	Summary: PMID:7902576 directly measured ATPase activity of yeast HSP60 (cpn60). The ATPase activity is intrinsic to the chaperonin folding cycle. Supporting Evidence: PMID:7902576 Identification and functional analysis of chaperonin 10, the groES homolog from yeast mitochondria. PMID:9256426 Hsp10 inhibits the ATPase activity of hsp60 by about 40%.
GO:0016887 ATP hydrolysis activity	IDA PMID:9256426 Significance of chaperonin 10-mediated inhibition of ATP hyd...	ACCEPT	Summary: PMID:9256426 demonstrated that HSP60 has ATPase activity that is inhibited approximately 40% by HSP10. This inhibition is mechanistically coupled to the folding cycle. Supporting Evidence: PMID:9256426 Hsp10 inhibits the ATPase activity of hsp60 by about 40%.
GO:0042026 protein refolding	IMP PMID:1359644 Prevention of protein denaturation under heat stress by the ...	ACCEPT	Summary: PMID:1359644 showed HSP60 mediates ATP-dependent refolding of heat-denatured DHFR in vitro, preventing aggregation and restoring activity. Supporting Evidence: PMID:1359644 Hsp60 bound to DHFR in the course of thermal denaturation, preventing its aggregation, and mediated its adenosine triphosphate-dependent refolding at increased temperatures.
GO:0042026 protein refolding	IDA PMID:9256426 Significance of chaperonin 10-mediated inhibition of ATP hyd...	ACCEPT	Summary: PMID:9256426 demonstrated in vitro refolding of mitochondrial malate dehydrogenase by purified HSP60/HSP10 in the presence of ATP. Supporting Evidence: PMID:9256426 In the presence of ATP, the purified yeast chaperonins mediate the refolding of mitochondrial malate dehydrogenase.
GO:0042645 mitochondrial nucleoid	IDA PMID:10869431 In organello formaldehyde crosslinking of proteins to mtDNA:...	KEEP AS NON CORE	Summary: Crosslinking study showing HSP60 associates with mtDNA. Consistent with role in nucleoid structure. Reason: Moonlighting function related to mtDNA maintenance.
GO:0045041 protein import into mitochondrial intermembrane space	IMP PMID:1347713 Antifolding activity of hsp60 couples protein import into th...	KEEP AS NON CORE	Summary: PMID:1347713 demonstrated that HSP60 antifolding activity couples protein import into the matrix with export to the intermembrane space. This is a downstream consequence of its chaperonin activity rather than a distinct function. Reason: Secondary to core chaperonin folding activity. Supporting Evidence: PMID:1347713 Antifolding activity of hsp60 couples protein import into the mitochondrial matrix with export to the intermembrane space. file:yeast/HSP60/HSP60-deep-research-falcon.md Yeast mitochondrial precursor proteins associate with Hsp60 as folding intermediates after import; ATP-dependent folding/release has been demonstrated in classical imported substrate experiments (e.g., Su9-DHFR) cited in major yeast chaperone reviews.
GO:0050821 protein stabilization	IMP PMID:1359644 Prevention of protein denaturation under heat stress by the ...	KEEP AS NON CORE	Summary: PMID:1359644 showed HSP60 prevents thermal inactivation of DHFR in vivo and prevents aggregation in vitro. Protein stabilization is a consequence of its chaperonin activity during heat stress. Reason: Consequence of chaperonin activity under stress, not a distinct core function. Supporting Evidence: PMID:1359644 The Hsp60 was required to prevent the thermal inactivation in vivo of native dihydrofolate reductase (DHFR) imported into mitochondria.
GO:0051087 protein-folding chaperone binding	IPI PMID:9256426 Significance of chaperonin 10-mediated inhibition of ATP hyd...	ACCEPT	Summary: PMID:9256426 directly measured HSP60-HSP10 binding with high affinity (Kd 0.9 nM). This interaction is central to the chaperonin folding mechanism. Supporting Evidence: PMID:9256426 In the presence of ADP, one molecule of hsp10 binds to hsp60 with an apparent Kd of 0.9 nM and a second molecule of hsp10 binds with a Kd of 24 nM.
GO:0051131 chaperone-mediated protein complex assembly	IMP PMID:2645524 Mitochondrial heat-shock protein hsp60 is essential for asse...	ACCEPT	Summary: PMID:2645524 demonstrated that HSP60 is essential for assembly of imported proteins into oligomeric complexes. This is a key aspect of its chaperonin function. Supporting Evidence: PMID:2645524 A nuclear encoded mitochondrial heat-shock protein hsp60 is required for the assembly into oligomeric complexes of proteins imported into the mitochondrial matrix.
GO:0051604 protein maturation	IMP PMID:8097278 Loss of mitochondrial hsp60 function: nonequivalent effects ...	KEEP AS NON CORE	Summary: PMID:8097278 studied loss of HSP60 function effects on matrix-targeted and intermembrane-targeted proteins, showing HSP60 is needed for proper maturation. This is a downstream consequence of its folding activity. Reason: Protein maturation is a downstream consequence of chaperonin-assisted folding.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-SCE-1252253	KEEP AS NON CORE	Summary: Reactome annotation based on TIM23 PAM complex translocation pathway. HSP60 participates in this process but is primarily a matrix protein. Reason: Association with inner membrane during protein import; primary location is matrix.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-SCE-1268014	KEEP AS NON CORE	Summary: Reactome annotation for precursor protein entry into TIM23 PAM complex. Same rationale as above. Reason: Association with inner membrane during protein import.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-SCE-1268017	KEEP AS NON CORE	Summary: Reactome annotation for MPP presequence hydrolysis. Same rationale. Reason: Association with inner membrane during protein import.
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-SCE-1252255	REMOVE	Summary: Reactome annotation suggesting HSP60 is in the intermembrane space during the TOM40/TOM70 translocation process. HSP60 is not a resident IMS protein; it participates in protein import that transits the IMS. Reason: HSP60 is not a resident IMS protein. This annotation reflects its transient role in the import pathway.
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-SCE-1268014	REMOVE	Summary: Same rationale as above. HSP60 is a matrix protein, not an IMS resident. Reason: HSP60 is not a resident IMS protein.
GO:0005759 mitochondrial matrix	TAS Reactome:R-SCE-1252253	ACCEPT	Summary: Reactome annotation consistent with known matrix localization.
GO:0005829 cytosol	TAS Reactome:R-SCE-1252255	REMOVE	Summary: Reactome annotation. HSP60 is synthesized in the cytosol but is rapidly imported into mitochondria. The cytosol is not where HSP60 functions. Reason: HSP60 functions in the mitochondrial matrix, not the cytosol. Cytosolic presence is only transient during import.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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