Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: HSP82/Hsp90 is a well-established protein folding chaperone. IBA annotation is consistent with the known function of this conserved chaperone family across eukaryotes. Falcon deep research frames Hsp82 as a selective proteostasis hub that assists late-stage folding, activation, and stability of specific client proteins rather than acting as a general chaperone for all misfolded proteins. Reason: Protein folding is a core biological process for Hsp90. UniProt describes HSP82 as a "Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins." Multiple IMP and IDA evidence codes confirm involvement in de novo protein folding (PMID:10564510, PMID:9371781). Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp82 (Hsp90) is an ATP-dependent molecular chaperone that assists the late-stage folding, activation, and stability of a large set of specific file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp90/Hsp82 is best understood as a proteostasis hub rather than a general chaperone for all misfolded proteins
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 has well-characterized ATPase activity essential for its chaperone cycle. IBA annotation is correct. Falcon deep research places ATP hydrolysis within the dimeric open/closed conformational cycle, noting that the constitutive paralog Hsc82 has somewhat higher ATPase activity than Hsp82 (~1.3-fold at 30C, ~1.6-fold at 37C), with kinetic differences mapping to N-terminal-domain substitutions near the nucleotide pocket. Reason: ATPase activity is fundamental to Hsp90 function. Directly demonstrated by IDA (PMID:12235160) and multiple structural studies showing ATP binding and hydrolysis. UniProt documents extensive mutagenesis data affecting ATPase activity (e.g., A41V causes 98% reduction, G83D abolishes activity). Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Client loading, conformational closing, ATP hydrolysis/nucleotide exchange, and reopening are regulated by co-chaperones that bind distinct surfaces and bias the timing of transitions file:yeast/HSP82/HSP82-deep-research-falcon.md Hsc82 exhibits higher ATPase activity than Hsp82 at both 30°C and 37°C in comparative assays, and kinetic differences map largely to N-terminal-domain substitutions near the nucleotide pocket
GO:0032991 protein-containing complex	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 functions as a homodimer and forms complexes with many co-chaperones and client proteins. Falcon deep research notes that yeast has roughly 14 Hsp90 co-chaperones with diverse domain architectures that target clients, modulate ATPase activity, and stabilize or destabilize conformational states. Reason: HSP82 is a homodimer and forms well-characterized complexes with co-chaperones (STI1, AHA1, SBA1, CDC37, CPR6, CPR7, CNS1, SSE1). Crystal structure of HSP82-SBA1-ATP closed complex (PDB:2CG9, PMID:16625188) confirms complex formation. ComplexPortal entry CPX-1276 (HMC complex) is documented. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Yeast has ~14 Hsp90 co-chaperones (diverse domain architectures) that target clients, modulate ATPase activity, and stabilize or destabilize conformational states
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for plasma membrane localization of HSP82. While Hsp90 is primarily cytoplasmic, some evidence exists for plasma membrane association in other organisms. Reason: HSP82 is primarily cytoplasmic (IDA PMID:32920053, PMID:27385335). Plasma membrane localization is not well-established for the yeast protein specifically, but the IBA inference from orthologs is plausible for a minor pool. Not a core localization.
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 binds ATP as part of its chaperone cycle. Well-established by crystallography. Reason: ATP binding is essential for Hsp90 function. Multiple crystal structures show ATP/ADP binding (PDB:1AM1, 1AMW, 2CG9). UniProt documents extensive ATP binding site residues. The functional cycle is linked to ATP binding and hydrolysis.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 is a cytosolic protein. IBA annotation is correct. Falcon deep research confirms that cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth. Reason: Consistent with IDA evidence for cytoplasm localization (PMID:32920053, PMID:27385335) and HDA data (PMID:11914276, PMID:14562095). Cytosol is the expected localization for Hsp90. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth
GO:0050821 protein stabilization	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 stabilizes client proteins as part of its chaperone function. IBA annotation is appropriate. Falcon deep research describes Hsp82 as assisting the late-stage folding, activation, and stability of a defined set of client proteins. Reason: Protein stabilization is a core function of Hsp90. IMP evidence shows HSP82 is required for protein maturation (PMID:27068472). UniProt states it "promotes the maturation, structural maintenance and proper regulation of specific target proteins." Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp82 (Hsp90) is an ATP-dependent molecular chaperone that assists the late-stage folding, activation, and stability of a large set of specific
GO:0034605 cellular response to heat	IBA GO_REF:0000033	ACCEPT	Summary: HSP82 is the heat-inducible Hsp90 isoform, centrally involved in heat stress response. Falcon deep research provides quantitative support: Hsp82 is very low at 25-30C and induced at 37C to levels similar to the constitutive Hsc82 paralog, and Hsp82 is more thermally stable than Hsc82 (Tm ~60.4C vs 57.1C), consistent with a stress-specialized role. Reason: HSP82 is named as a heat shock protein precisely because it is induced by heat stress. UniProt confirms it is "required for growth at high temperatures" (PMID:2674684). The gene name itself (HSP82 = Heat Shock Protein 82) reflects this core function. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp82 is very low at 25–30°C and induced at 37°C to levels similar to Hsc82, consistent with a stress-specialized role file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp82 is more thermally stable than Hsc82 (Tm ~60.4°C vs 57.1°C)
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 is proposed for obsoletion. HSP82 does interact with unfolded/misfolded client proteins but its mechanism is better captured by GO:0140662 (ATP-dependent protein folding chaperone). Reason: GO:0051082 is proposed for obsoletion. HSP82 is an ATP-dependent foldase; while it does bind unfolded/non-native proteins as part of its chaperone cycle, the binding is coupled to ATP-driven conformational changes. The more appropriate term is GO:0140662 "ATP-dependent protein folding chaperone" which captures both the binding and the active folding mechanism. IDA evidence from PMID:10564510 demonstrated binding to denatured substrates, but this is part of the broader chaperone activity. Proposed replacements: ATP-dependent protein folding chaperone
GO:0048471 perinuclear region of cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for perinuclear localization. HSP82 is primarily cytoplasmic with some nuclear presence; perinuclear enrichment is plausible from ortholog data. Reason: HSP82 is found in both cytoplasm and nucleus (IDA PMID:32920053). Perinuclear localization is inferred from orthologs and may represent a minor pool. Not a primary localization.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. Broader than ATP binding but not incorrect. Reason: Nucleotide binding is a parent term of ATP binding. While more specific IBA and IEA annotations for ATP binding exist, this broader IEA annotation is not incorrect and reflects the UniProt keyword mapping. It is redundant with the more specific ATP binding annotation but acceptable.
GO:0000492 box C/D snoRNP assembly	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine learning prediction for snoRNP assembly involvement. Supported by IMP evidence. Reason: Supported by IMP evidence (PMID:18268103) which showed Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. This is a legitimate but secondary function of Hsp90, mediated through its general chaperone role on client proteins in the R2TP pathway.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP binding from InterPro/ARBA. Consistent with IBA and experimental evidence. Reason: Redundant with IBA annotation but correct. ATP binding is a core molecular function of HSP82.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for cytoplasm from UniProt subcellular location mapping. Correct. Reason: Consistent with multiple IDA and HDA evidence for cytoplasmic localization.
GO:0006457 protein folding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for protein folding. Redundant with IBA but correct. Reason: Consistent with IBA and experimental annotations for protein folding involvement.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP hydrolysis activity. Redundant with IBA and IDA but correct. Reason: Consistent with IBA and IDA (PMID:12235160) annotations for ATPase activity.
GO:0043248 proteasome assembly	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA prediction for proteasome assembly involvement. Supported by IDA/IMP evidence. Reason: Supported by experimental evidence (IDA and IMP, PMID:12853471). HSP82 assists in proteasome assembly as one of its client-dependent functions. Not a core function of HSP82 per se, but a legitimate downstream consequence of its chaperone activity.
GO:0051082 unfolded protein binding	IEA GO_REF:0000120	MODIFY	Summary: IEA annotation for unfolded protein binding. Same issue as IBA annotation - term proposed for obsoletion. Reason: GO:0051082 is proposed for obsoletion. Should be replaced with GO:0140662 "ATP-dependent protein folding chaperone" which better captures the active chaperone mechanism. Proposed replacements: ATP-dependent protein folding chaperone
GO:0140662 ATP-dependent protein folding chaperone	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro for ATP-dependent protein folding chaperone. This is the correct and most informative molecular function term for HSP82. Falcon deep research describes Hsp82 as a dimeric chaperone cycling between an open (C-terminally dimerized) state and an ATP-induced closed state with additional N-terminal contacts. Reason: GO:0140662 is the ideal molecular function term for HSP82/Hsp90. It captures both the ATP dependence and the protein folding chaperone activity. HSP82 binds to client proteins and assists their folding through an ATP-dependent conformational cycle. This should be considered the primary MF annotation for HSP82. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Yeast Hsp90 (Hsp82/Hsc82) is a dimeric chaperone cycling between file:yeast/HSP82/HSP82-deep-research-falcon.md an ATP-induced closed state with additional N-terminal contacts
GO:0005515 protein binding	IPI PMID:11805837 Systematic identification of protein complexes in Saccharomy...	MARK AS OVER ANNOTATED	Summary: IPI from large-scale mass spectrometry study. Uninformative "protein binding" annotation. Reason: "Protein binding" is uninformative for a molecular chaperone that by definition binds many proteins. HSP82 interacts with dozens of co-chaperones and client proteins. The more informative annotation is GO:0140662 (ATP-dependent protein folding chaperone). Large-scale interaction studies produce many IPI annotations that do not capture specific molecular functions.
GO:0005515 protein binding	IPI PMID:12604615 Aha1 binds to the middle domain of Hsp90, contributes to cli...	MARK AS OVER ANNOTATED	Summary: IPI from study of Aha1 binding to Hsp90. Specific interaction with co-chaperone. Reason: While the interaction with Aha1 is genuine and important for the chaperone cycle, "protein binding" is uninformative. The chaperone function is better captured by GO:0140662.
GO:0005515 protein binding	IPI PMID:14729968 The ctf13-30/CTF13 genomic haploinsufficiency modifier scree...	MARK AS OVER ANNOTATED	Summary: IPI from ctf13/RSC study. Generic protein binding annotation. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:15102838 A novel mode of chaperone action: heme activation of Hap1 by...	MARK AS OVER ANNOTATED	Summary: IPI from Hap1 interaction study. HSP82 interacts with the transcription factor Hap1. Reason: While HSP82-Hap1 interaction is genuine, "protein binding" is uninformative for a chaperone.
GO:0005515 protein binding	IPI PMID:15766533 Navigating the chaperone network: an integrative map of phys...	MARK AS OVER ANNOTATED	Summary: IPI from large-scale chaperone network study (Zhao et al 2005). Many interactions detected. Reason: Large-scale study detecting many chaperone-client and chaperone-cochaperone interactions. "Protein binding" is uninformative for a chaperone.
GO:0005515 protein binding	IPI PMID:15879519 A two-hybrid screen of the yeast proteome for Hsp90 interact...	MARK AS OVER ANNOTATED	Summary: IPI from yeast two-hybrid screen for Hsp90 interactors. Reason: Uninformative "protein binding" for a chaperone with extensive interaction network.
GO:0005515 protein binding	IPI PMID:16407978 The phosphatase Ppt1 is a dedicated regulator of the molecul...	MARK AS OVER ANNOTATED	Summary: IPI from Ppt1 phosphatase study. Ppt1 is a dedicated regulator of Hsp90. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:16429126 Proteome survey reveals modularity of the yeast cell machine...	MARK AS OVER ANNOTATED	Summary: IPI from proteome survey. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:16554755 Global landscape of protein complexes in the yeast Saccharom...	MARK AS OVER ANNOTATED	Summary: IPI from large-scale protein complex study (Krogan et al 2006). Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:16625188 Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed cha...	MARK AS OVER ANNOTATED	Summary: IPI from crystal structure of HSP82-SBA1-nucleotide complex. Reason: While the SBA1 interaction is structurally characterized, "protein binding" is uninformative.
GO:0005515 protein binding	IPI PMID:18268103 Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain ...	MARK AS OVER ANNOTATED	Summary: IPI from R2TP complex/snoRNP assembly study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:18719252 High-quality binary protein interaction map of the yeast int...	MARK AS OVER ANNOTATED	Summary: IPI from high-quality binary interaction map. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:18818696 Structural and functional coupling of Hsp90- and Sgt1-centre...	MARK AS OVER ANNOTATED	Summary: IPI from Sgt1 complex study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:18833289 Structural and functional analysis of SGT1-HSP90 core comple...	MARK AS OVER ANNOTATED	Summary: IPI from protein interaction study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ...	MARK AS OVER ANNOTATED	Summary: IPI from atlas of chaperone-protein interactions. Reason: Uninformative "protein binding" for a chaperone. This study itself maps the chaperone interaction network.
GO:0005515 protein binding	IPI PMID:21170051 Mixed Hsp90-cochaperone complexes are important for the prog...	MARK AS OVER ANNOTATED	Summary: IPI from mixed Hsp90-cochaperone complex study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:21734642 Combinatorial depletion analysis to assemble the network arc...	MARK AS OVER ANNOTATED	Summary: IPI from SAGA/ADA complex study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:21892170 Structural analysis of the interaction between Hsp90 and the...	MARK AS OVER ANNOTATED	Summary: IPI from structural analysis of Hsp90-p53 interaction. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:23217712 CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abund...	MARK AS OVER ANNOTATED	Summary: IPI from CDK-dependent Hsp70 phosphorylation study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:23396352 Integration of the accelerator Aha1 in the Hsp90 co-chaperon...	MARK AS OVER ANNOTATED	Summary: IPI from Aha1 integration into Hsp90 co-chaperone cycle study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:24012479 High-resolution structural analysis shows how Tah1 tethers H...	MARK AS OVER ANNOTATED	Summary: IPI from protein interaction study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:24794838 Structural basis for phosphorylation-dependent recruitment o...	MARK AS OVER ANNOTATED	Summary: IPI from Tel2-Hsp90-Pih1 structural study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:31454312 The role of structural pleiotropy and regulatory evolution i...	MARK AS OVER ANNOTATED	Summary: IPI from structural pleiotropy study of Hsp90 paralogs. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:37968396 The social and structural architecture of the yeast protein ...	MARK AS OVER ANNOTATED	Summary: IPI from yeast protein interactome architecture study. Reason: Uninformative "protein binding" for a chaperone.
GO:0005515 protein binding	IPI PMID:9817749 In vivo function of Hsp90 is dependent on ATP binding and AT...	MARK AS OVER ANNOTATED	Summary: IPI from study showing Hsp90 function depends on ATP binding and hydrolysis. Reason: Uninformative "protein binding" for a chaperone. The actual finding is about ATP-dependent chaperone function, not generic protein binding.
GO:0005515 protein binding	IPI PMID:9819422 Cns1 is an essential protein associated with the hsp90 chape...	MARK AS OVER ANNOTATED	Summary: IPI from Cns1/CPR7 interaction study. Reason: Uninformative "protein binding" for a chaperone.
GO:0042802 identical protein binding	IPI PMID:16625188 Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed cha...	ACCEPT	Summary: HSP82 forms homodimers as part of its functional cycle. The crystal structure (PDB:2CG9) confirms dimerization. Falcon deep research describes yeast Hsp90 as a dimeric chaperone whose open state is C-terminally dimerized, with the conserved co-chaperone-binding motif at the C-terminus. Reason: Homodimerization is essential for Hsp90 function. The crystal structure of the closed chaperone complex (PMID:16625188) directly shows the dimer. This is a core structural feature of Hsp90. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md an open state (C-terminally dimerized) and file:yeast/HSP82/HSP82-deep-research-falcon.md C-terminal dimerization domain including the conserved co-chaperone-binding motif at the C-terminus
GO:0042802 identical protein binding	IPI PMID:18268103 Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain ...	ACCEPT	Summary: Additional evidence for HSP82 homodimerization. Reason: Consistent with known Hsp90 dimerization. Duplicate annotation with different reference is fine.
GO:0042802 identical protein binding	IPI PMID:19696785 Hsp90 is regulated by a switch point in the C-terminal domai...	ACCEPT	Summary: HSP82 homodimerization via C-terminal domain switch point study. Reason: C-terminal domain dimerization dynamics are important for the conformational cycle. Mutagenesis of A577 modulates dimerization, ATPase, and client activation.
GO:0042802 identical protein binding	IPI PMID:20736353 Dynamics of heat shock protein 90 C-terminal dimerization is...	ACCEPT	Summary: HSP82 C-terminal dimerization dynamics study. Reason: Further confirmation of homodimerization as essential for the conformational cycle.
GO:0042802 identical protein binding	IPI PMID:23396352 Integration of the accelerator Aha1 in the Hsp90 co-chaperon...	ACCEPT	Summary: HSP82 homodimerization in context of Aha1 co-chaperone cycle. Reason: Consistent with known Hsp90 dimerization.
GO:0042802 identical protein binding	IPI PMID:24794838 Structural basis for phosphorylation-dependent recruitment o...	ACCEPT	Summary: HSP82 homodimerization in Tel2-Hsp90-Pih1 study. Reason: Consistent with known Hsp90 dimerization.
GO:0042802 identical protein binding	IPI PMID:31454312 The role of structural pleiotropy and regulatory evolution i...	ACCEPT	Summary: HSP82 homodimerization in paralog heteromer study. Reason: Consistent with known Hsp90 dimerization and also documents HSP82-HSC82 heterodimerization.
GO:0070482 response to oxygen levels	NAS PMID:9632766 Molecular mechanism governing heme signaling in yeast: a hig...	KEEP AS NON CORE	Summary: NAS annotation from ComplexPortal, based on HSP82 involvement in HAP1-mediated heme signaling. Reason: HSP82 forms a complex with HAP1, a transcriptional activator regulated by heme (proxy for oxygen). This is a client-dependent function. The NAS evidence is weak but the underlying biology is supported by UniProt documentation of HSP82-HAP1 interaction (PMID:9632766).
GO:0005634 nucleus	IDA PMID:32920053 A Single Site Phosphorylation on Hsp82 Ensures Cell Survival...	KEEP AS NON CORE	Summary: IDA evidence for nuclear localization from starvation phosphorylation study. Falcon deep research reinforces a condition-dependent nuclear pool: Hsp90 (with the co-chaperone Sba1/p23) accumulates in the nucleus in quiescent cells (glucose exhaustion) and in sporulating diploids, where nuclear accumulation defects correlate with sporulation/spore-wall defects. Reason: HSP82 is primarily cytoplasmic but a nuclear pool exists, enhanced during starvation, quiescence, and sporulation. The starvation study (PMID:32920053) showed phosphorylation-dependent nuclear localization, and falcon deep research corroborates condition-dependent nuclear accumulation (Tapia & Morano 2010). Nuclear localization remains a regulated, non-core compartment rather than the primary site of action. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md accumulates in the nucleus in quiescent cells (glucose exhaustion) and in sporulating diploids
GO:0005737 cytoplasm	IDA PMID:32920053 A Single Site Phosphorylation on Hsp82 Ensures Cell Survival...	ACCEPT	Summary: IDA evidence for cytoplasmic localization. Reason: Core localization of HSP82. Consistent with multiple lines of evidence.
GO:0016887 ATP hydrolysis activity	IDA PMID:12235160 N-terminal residues regulate the catalytic efficiency of the...	ACCEPT	Summary: Direct assay evidence for ATPase activity of HSP82. Reason: Core molecular function. Direct biochemical measurement of ATPase activity.
GO:0016887 ATP hydrolysis activity	IMP PMID:27068472 Systematic Mutant Analyses Elucidate General and Client-Spec...	ACCEPT	Summary: Mutant phenotype evidence for ATPase activity from systematic mutant analysis. Reason: Systematic mutant analysis showing ATPase activity is required for client-specific and general Hsp90 functions. Complements IDA evidence.
GO:0005737 cytoplasm	HDA PMID:11914276 Subcellular localization of the yeast proteome.	ACCEPT	Summary: High-throughput data for cytoplasmic localization. Reason: Consistent with IDA evidence.
GO:0005737 cytoplasm	HDA PMID:14562095 Global analysis of protein localization in budding yeast.	ACCEPT	Summary: High-throughput GFP localization data confirming cytoplasm. Reason: Global protein localization study. Consistent with IDA evidence.
GO:0005737 cytoplasm	IDA PMID:27385335 Detection of protein-protein interactions at the septin coll...	ACCEPT	Summary: IDA from split-GFP system at septin collar. Reason: Consistent with cytoplasmic localization.
GO:0051604 protein maturation	IMP PMID:27068472 Systematic Mutant Analyses Elucidate General and Client-Spec...	ACCEPT	Summary: IMP evidence from systematic mutant analysis showing HSP82 is required for protein maturation. Reason: UniProt describes HSP82 as promoting "the maturation, structural maintenance and proper regulation of specific target proteins." Protein maturation is a core function of Hsp90.
GO:0000492 box C/D snoRNP assembly	IMP PMID:18268103 Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain ...	KEEP AS NON CORE	Summary: IMP evidence showing Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex for snoRNP assembly. Reason: Hsp90 acts on the R2TP pathway components (Pih1, Tah1) that are required for snoRNP assembly. This is a legitimate client-dependent function but not a core function of HSP82.
GO:0006458 'de novo' protein folding	IDA PMID:10564510 Contribution of N- and C-terminal domains to the function of...	ACCEPT	Summary: Direct assay evidence for de novo protein folding by HSP82. Falcon deep research emphasizes that this is selective: Hsp90/Hsp82 supports refolding/activation of specific substrates (e.g., luciferase) rather than acting as a general chaperone for all misfolded proteins. Reason: Study of N- and C-terminal domain contributions to Hsp90 function in S. cerevisiae. Demonstrates involvement in de novo protein folding. Supporting Evidence: file:yeast/HSP82/HSP82-deep-research-falcon.md Hsp90/Hsp82 is best understood as a proteostasis hub rather than a general chaperone for all misfolded proteins
GO:0006458 'de novo' protein folding	IMP PMID:9371781 In vivo functions of the Saccharomyces cerevisiae Hsp90 chap...	ACCEPT	Summary: IMP evidence for de novo protein folding from in vivo function study. Reason: Study of in vivo functions of Hsp90 in S. cerevisiae. Demonstrates role in de novo protein folding through mutant analysis.
GO:0006970 response to osmotic stress	IMP PMID:16487343 The molecular chaperone Hsp90 is required for high osmotic s...	KEEP AS NON CORE	Summary: IMP evidence showing Hsp90 is required for high osmotic stress response. Reason: Hsp90 is required for the osmotic stress response, likely through chaperoning stress-responsive kinases (e.g., Hog1 pathway clients). This is a stress-responsive function but secondary to the core chaperone activity.
GO:0032212 positive regulation of telomere maintenance via telomerase	IDA PMID:17954556 The hsp90 molecular chaperone modulates multiple telomerase ...	KEEP AS NON CORE	Summary: IDA evidence for positive regulation of telomere maintenance via telomerase. Reason: Hsp90 modulates multiple telomerase activities. This is a client-dependent function where Hsp90 chaperones telomerase components. Not a core function of HSP82 itself.
GO:0032212 positive regulation of telomere maintenance via telomerase	IMP PMID:17954556 The hsp90 molecular chaperone modulates multiple telomerase ...	KEEP AS NON CORE	Summary: IMP evidence for telomerase regulation. Reason: Complements IDA evidence. Client-dependent function.
GO:0042026 protein refolding	IMP PMID:9371781 In vivo functions of the Saccharomyces cerevisiae Hsp90 chap...	ACCEPT	Summary: IMP evidence for protein refolding activity from in vivo function study. Reason: Protein refolding is a core function of Hsp90. The in vivo study demonstrates this capacity.
GO:0043248 proteasome assembly	IDA PMID:12853471 The molecular chaperone Hsp90 plays a role in the assembly a...	KEEP AS NON CORE	Summary: IDA evidence for proteasome assembly involvement. Reason: HSP82 assists in proteasome assembly as a client-dependent function. The chaperone assists proteasome maturation but this is secondary to its core function.
GO:0043248 proteasome assembly	IMP PMID:12853471 The molecular chaperone Hsp90 plays a role in the assembly a...	KEEP AS NON CORE	Summary: IMP evidence for proteasome assembly. Reason: Complements IDA evidence. Client-dependent function.
GO:0051082 unfolded protein binding	IDA PMID:10564510 Contribution of N- and C-terminal domains to the function of...	MODIFY	Summary: IDA evidence showing HSP82 binds unfolded/denatured proteins. Term proposed for obsoletion. Reason: While the experimental evidence is solid (HSP82 does bind unfolded proteins as shown by PMID:10564510), GO:0051082 is proposed for obsoletion. The binding of unfolded proteins is part of the ATP-dependent chaperone mechanism, better captured by GO:0140662 "ATP-dependent protein folding chaperone." Proposed replacements: ATP-dependent protein folding chaperone
GO:0032204 regulation of telomere maintenance	IMP PMID:21829731 HSP90 controls SIR2 mediated gene silencing.	KEEP AS NON CORE	Summary: IMP evidence from CACAO annotation showing HSP90 controls SIR2-mediated gene silencing and telomere maintenance. Reason: HSP90 controls SIR2-mediated gene silencing which affects telomere maintenance. This is another example of a client-dependent function. Secondary to core chaperone activity.

Core Functions

Primary molecular function: ATP-dependent protein folding chaperone. HSP82 binds to client proteins and assists their folding through an ATP-dependent conformational cycle. Supported by IEA from InterPro, IDA evidence for ATP hydrolysis (PMID:12235160), unfolded protein binding (PMID:10564510), and de novo protein folding (PMID:10564510). Crystal structures confirm ATP-dependent conformational cycle (PDB:2CG9).

Molecular Function:

ATP-dependent protein folding chaperone

Directly Involved In:

protein folding cellular response to heat

Cellular Locations:

cytoplasm

ATPase activity is fundamental to the Hsp90 chaperone cycle. Directly demonstrated by IDA (PMID:12235160) and IMP (PMID:27068472). Extensive mutagenesis data documents residues critical for ATPase activity.

Molecular Function:

ATP hydrolysis activity

Directly Involved In:

protein folding

Cellular Locations:

cytoplasm

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

Hsp82 is annotated to ATP-dependent protein folding chaperone (GO:0140662) and protein folding (GO:0006457) via InterPro-to-GO mapping reflecting Hsp90 family membership.

GO_REF:0000033

Annotation inferences using phylogenetic trees

PANTHER phylogenetic-tree annotation propagates conserved Hsp90 chaperone functions (ATP binding, ATP hydrolysis, protein folding, cellular response to heat, protein stabilization, identical protein binding, cytosol localization) to S. cerevisiae HSP82.

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

UniProtKB keyword 'Nucleotide-binding' maps to GO:0000166 nucleotide binding for HSP82 based on its conserved Hsp90 ATPase domain.

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

HSP82 UniProt subcellular location annotation (cytoplasm) is mapped to GO:0005737 cytoplasm.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

ARBA machine-learning model assigns HSP82 to box C/D snoRNP assembly and proteasome assembly based on Hsp90 family signatures and chaperone client patterns.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

Combined automated IEA pipelines annotate HSP82 with ATP binding, ATP hydrolysis activity, protein folding, and unfolded protein binding from UniProt features.

PMID:10564510

Contribution of N- and C-terminal domains to the function of Hsp90 in Saccharomyces cerevisiae.

Direct evidence for de novo protein folding and unfolded protein binding by HSP82

PMID:11805837

Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry.

HSP82 was identified as part of multi-protein complexes in S. cerevisiae by systematic affinity purification-mass spectrometry; supports broad protein-binding annotations of HSP82 as a chaperone hub.

PMID:11914276

Subcellular localization of the yeast proteome.

Subcellular localization survey assigns HSP82 to the cytoplasm in S. cerevisiae, consistent with its predominant cytosolic chaperone role.

PMID:12235160

N-terminal residues regulate the catalytic efficiency of the Hsp90 ATPase cycle.

Direct biochemical assay of ATPase activity

PMID:12604615

Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone.

Aha1 binds the middle domain of Hsp90 (HSP82), stimulates ATPase activity, and contributes to client protein activation, anchoring HSP82 in the canonical Hsp90 co-chaperone cycle.

PMID:12853471

The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome.

HSP82/Hsp90 is required for assembly and maintenance of the 26S proteasome in vivo, supporting GO:0043248 proteasome assembly as a client-dependent secondary function.

"Functional loss of Hsp90 using a temperature-sensitive mutant in yeast caused dissociation of the 26S proteasome."

PMID:14562095

Global analysis of protein localization in budding yeast.

Genome-wide GFP localization study assigns HSP82 to the cytoplasm in S. cerevisiae.

PMID:14729968

The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion.

This paper supports the IPI annotation of HSP82 to protein binding (GO:0005515) but does not provide visible abstract-level evidence for HSP82 function; the IPI annotation is correctly flagged MARK_AS_OVER_ANNOTATED in this review.

PMID:15102838

A novel mode of chaperone action: heme activation of Hap1 by enhanced association of Hsp90 with the repressed Hsp70-Hap1 complex.

HSP82/Hsp90 activates the heme-regulated transcription factor Hap1 by enhancing association with the repressed Hsp70-Hap1 complex; demonstrates client-specific chaperone action.

PMID:15766533

Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone.

Integrative map of HSP82/Hsp90 physical and genetic interactions defines its central position in the yeast chaperone network.

PMID:15879519

A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p).

Yeast two-hybrid screen of the proteome identifies many HSP82/Hsp90 interactors, supporting its role as a chaperone hub.

PMID:16407978

The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90.

The phosphatase Ppt1 is a dedicated regulator of HSP82/Hsp90 chaperone activity, identifying a specific co-chaperone-like interaction.

PMID:16429126

Proteome survey reveals modularity of the yeast cell machinery.

Proteome survey of yeast cellular machinery places HSP82 within multi-protein modules consistent with its chaperone hub status.

PMID:16487343

The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae.

HSP82/Hsp90 is required for the high osmotic stress response in S. cerevisiae, supporting GO:0006970 response to osmotic stress as a client-dependent function.

PMID:16554755

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.

HSP82 is part of the global landscape of yeast protein complexes mapped by tandem affinity purification.

PMID:16625188

Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.

Crystal structure of full-length Hsp82 dimer in closed conformation with SBA1 and ATP

"Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1."

PMID:17954556

The hsp90 molecular chaperone modulates multiple telomerase activities.

HSP82/Hsp90 modulates multiple telomerase activities, supporting its role in positive regulation of telomere maintenance via telomerase as a client-dependent function.

PMID:18268103

Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation.

HSP82/Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation, providing IMP evidence for box C/D snoRNP assembly involvement.

"Together with the Tah1 cofactor, Hsp90 functions to stabilize Pih1. As a consequence, the chaperone is shown to affect box C/D accumulation and maintenance, especially under stress conditions."

PMID:18719252

High-quality binary protein interaction map of the yeast interactome network.

HSP82 is captured in a high-quality binary interaction map of the yeast interactome.

PMID:18818696

Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes.

Structural and functional studies couple HSP82/Hsp90 to Sgt1-centered multi-protein complexes (yeast-specific Sgt1-Hsp90 interaction), supporting its co-chaperone-mediated client recruitment.

PMID:18833289

Structural and functional analysis of SGT1-HSP90 core complex required for innate immunity in plants.

Plant SGT1-HSP90 structural/functional study; cited here for cross-species context on conserved Hsp90 chaperone-cochaperone scaffolding rather than direct yeast HSP82 evidence (yeast-specific Sgt1-Hsp90 interaction is documented in PMID:18818696).

PMID:19536198

An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell.

Yeast atlas of chaperone-protein interactions defines HSP82's extensive chaperone-client and chaperone-cochaperone interaction network.

PMID:19696785

Hsp90 is regulated by a switch point in the C-terminal domain.

Hsp82 is regulated by a C-terminal switch-point that modulates dimerization, ATPase, and client activation; supports identical protein binding (homodimerization) annotations.

PMID:20736353

Dynamics of heat shock protein 90 C-terminal dimerization is an important part of its conformational cycle.

C-terminal dimerization dynamics of HSP82 are an integral part of its conformational cycle, providing additional support for homodimerization (GO:0042802).

PMID:21170051

Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.

Mixed Hsp82-cochaperone complexes are important for progression of the chaperone reaction cycle, supporting integration of HSP82 in dynamic multi-protein assemblies.

PMID:21734642

Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes.

HSP82 was detected in combinatorial depletion analyses assembling the SAGA/ADA chromatin remodeling complex network, consistent with broad interactome.

PMID:21829731

HSP90 controls SIR2 mediated gene silencing.

HSP90 controls SIR2-mediated gene silencing, supporting client-dependent regulation of telomere maintenance and chromatin silencing.

PMID:21892170

Structural analysis of the interaction between Hsp90 and the tumor suppressor protein p53.

Structural analysis of HSP82-p53 interaction characterizes a client-binding interface relevant to Hsp90's tumor-suppressor chaperone activity.

PMID:23217712

CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression.

CDK-dependent Hsp70 phosphorylation controls G1 cyclin abundance, with HSP82 contributing to cell-cycle progression via its co-chaperone partnership with Hsp70.

PMID:23396352

Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle.

Aha1 integrates as an accelerator of the HSP82/Hsp90 co-chaperone cycle, providing biochemical/structural support for ATPase regulation.

PMID:24012479

High-resolution structural analysis shows how Tah1 tethers Hsp90 to the R2TP complex.

High-resolution structural analysis shows that Tah1 tethers HSP82/Hsp90 to the R2TP complex, supporting client recruitment to snoRNP/RNA polymerase II-related assemblies.

PMID:24794838

Structural basis for phosphorylation-dependent recruitment of Tel2 to Hsp90 by Pih1.

Structural basis for phosphorylation-dependent recruitment of Tel2 to HSP82/Hsp90 by Pih1 supports HSP82's role in TTT-R2TP-mediated kinase chaperoning.

PMID:27068472

Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function.

Systematic mutant analysis of Hsp90 function

PMID:27385335

Detection of protein-protein interactions at the septin collar in Saccharomyces cerevisiae using a tripartite split-GFP system.

Tripartite split-GFP system places HSP82 at the septin collar in S. cerevisiae, supporting cytoplasmic localization with sub-cellular specificity.

PMID:31454312

The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs.

Structural pleiotropy and regulatory evolution maintain HSP82-HSC82 paralog heteromers, providing further support for identical protein binding (homo- and heterodimerization).

PMID:32920053

A Single Site Phosphorylation on Hsp82 Ensures Cell Survival during Starvation in Saccharomyces cerevisiae.

Single-site phosphorylation on HSP82 governs nuclear redistribution during starvation; supports both cytoplasmic and nuclear pools of HSP82.

"Ppt1 regulates Hsp82 distribution in the cytoplasm and nucleus by dephosphorylating the S485 residue on Hsp82."

PMID:37968396

The social and structural architecture of the yeast protein interactome.

HSP82 is part of the social/structural architecture of the yeast protein interactome captured by integrative network analysis.

PMID:9371781

In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone.

In vivo demonstration of protein folding and refolding functions

"The data suggest that Hsp90 is not required for the de novo folding of most proteins, but it is required for a specific subset of proteins that have greater difficulty reaching their native conformations."

PMID:9632766

Molecular mechanism governing heme signaling in yeast: a higher-order complex mediates heme regulation of the transcriptional activator HAP1.

HSP82 forms a higher-order complex that mediates heme regulation of the transcriptional activator HAP1, supporting client-dependent response to oxygen levels.

PMID:9817749

In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis.

In vivo Hsp82 function is dependent on ATP binding and ATP hydrolysis, anchoring the ATPase cycle as essential for cellular chaperone activity.

PMID:9819422

Cns1 is an essential protein associated with the hsp90 chaperone complex in Saccharomyces cerevisiae that can restore cyclophilin 40-dependent functions in cpr7Delta cells.

Cns1 is an essential Hsp82-associated co-chaperone that can restore cyclophilin 40-dependent functions in cpr7Delta cells, supporting HSP82 cochaperone-network annotations.

PMID:2674684

hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures.

HSP82 is essential and required at higher concentrations for growth at elevated temperatures

file:yeast/HSP82/HSP82-deep-research-falcon.md

Falcon deep research report on yeast HSP82 (Hsp90)

Hsp82 is an ATP-dependent molecular chaperone that assists late-stage folding, activation, and stability of a defined set of specific client proteins, acting as a selective proteostasis hub rather than a general chaperone for all misfolded proteins.

"Hsp82 (Hsp90) is an **ATP-dependent molecular chaperone** that assists the **late-stage folding, activation, and stability** of a large set of specific “client” proteins (substrates), including many signaling regulators (notably protein kinases and transcription factors)."
Yeast Hsp90 (Hsp82/Hsc82) is a dimeric chaperone cycling between an open, C-terminally dimerized state and an ATP-induced closed state with additional N-terminal contacts, regulated by co-chaperones.

"Yeast Hsp90 (Hsp82/Hsc82) is a **dimeric** chaperone cycling between: - an **open** state (C-terminally dimerized) and - an **ATP-induced closed** state with additional N-terminal contacts."
Yeast has approximately 14 Hsp90 co-chaperones that target clients, modulate ATPase activity, and stabilize or destabilize conformational states; Sti1/Hop targets clients to open Hsp90, Sba1/p23 stabilizes closed states, Aha1 stimulates ATP hydrolysis, and Cdc37 targets kinases.

"Yeast has ~14 Hsp90 co-chaperones (diverse domain architectures) that **target clients**, **modulate ATPase activity**, and **stabilize or destabilize** conformational states:"
HSP82 is the heat-inducible cytosolic Hsp90 isoform: very low at 25-30C and induced at 37C to levels similar to the constitutive Hsc82, consistent with a stress-specialized role.

"**Hsp82 is very low at 25–30°C and induced at 37°C to levels similar to Hsc82**, consistent with a stress-specialized role."
Hsp82 is more thermally stable than Hsc82 (Tm ~60.4C vs 57.1C) and shows superior refolding (~29% vs ~14% full refolding events in single-molecule assays), while Hsc82 has somewhat higher ATPase activity, reflecting isoform specialization mapping to the N-terminal domain.

"Hsp82 is **more thermally stable** than Hsc82 (Tm ~60.4°C vs 57.1°C). (girstmair2019thehsp90isoforms pages 1-2, girstmair2019thehsp90isoforms media 00261b28)"
Hsp90 is required for basal and pheromone-induced MAPK signaling in yeast, with Ste11 (the yeast Raf-equivalent MAPKKK) identified as a key endogenous client/substrate required for pathway accumulation and function.

"**MAPK/pheromone signaling:** Hsp90 is required for basal and pheromone-induced MAPK signaling, with **Ste11 (yeast Raf-equivalent MAPKKK)** identified as a key endogenous Hsp90 client/substrate required for accumulation and pathway function."
The HSP82/HSC82 family is essential: single deletion is viable but double disruption is lethal, and at least one cytosolic Hsp90 isoform is required for viability.

"Classic yeast genetics and biochemistry established that the HSP82/HSC82 family is **essential** (double disruption lethal), and that Hsp90 supports key signaling regulators."
Cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth but accumulates in the nucleus in quiescent cells (glucose exhaustion) and in sporulating diploids, where nuclear accumulation defects correlate with sporulation/spore-wall defects.

"**Condition-dependent nuclear accumulation:** A key cell-biological finding is that Hsp90 (and the cochaperone Sba1/p23) **accumulates in the nucleus in quiescent cells (glucose exhaustion)** and in sporulating diploids; nuclear accumulation defects correlate with **sporulation/spore-wall defects**, and pharmacological inhibition (macbecin) similarly disrupts nuclear accumulation and spore development."

Suggested Experiments

Experiment: Deplete or inhibit HSP82 (e.g., temperature-sensitive alleles, radicicol) and use AP-MS to map condition-dependent client losses, comparing standard growth to heat shock and starvation conditions to dissect core vs. stress-specific clientele.

Experiment: Reconstitute the full Hsp82 conformational cycle in vitro with purified HSP82 dimers, ATP, and a panel of co-chaperones (Sti1, Aha1, Sba1, Cdc37, Cpr6/7, Cns1) plus a model client kinase, and use single-molecule FRET to measure ATP-dependent open/closed dwell times.

Experiment: Generate separation-of-function HSP82 alleles that selectively impair ATPase, dimerization, or co-chaperone binding (using systematic mutagenesis of the M-domain) and measure client-specific phenotypes (e.g., HAP1, telomerase, R2TP, proteasome) to dissect contributions to each downstream pathway.

Deep Research

Falcon

(HSP82-deep-research-falcon.md)

Research Report: Functional Annotation of *S. cerevisiae* **HSP82** (UniProt P02829) Falcon Edison Scientific Literature 25 citations 2 artifacts 2026-05-30T09:54:55.530562

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000035 The Hsp90/Hsp82 domain architecture is summarized in the schematic in Figure 3d, which illustrates the N-terminal domain (NTD), mid (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of S. cerevisiae HSP82 (UniProt P02829)

0) Target identity verification (mandatory)

Verified target: UniProt P02829 corresponds to the Saccharomyces cerevisiae cytosolic Hsp90 heat-inducible isoform Hsp82 (gene HSP82). A 2024 yeast-focused review explicitly maps Hsp82 to UniProt P02829 and distinguishes the paralog Hsc82 as a separate cytosolic Hsp90 isoform. (rios2024insightsintohsp90 pages 1-2)

Paralog distinction: Yeast has two closely related cytosolic Hsp90 isoforms, the constitutive Hsc82 and stress-inducible Hsp82, sharing ~97% amino-acid identity but exhibiting measurable functional differences. (girstmair2019thehsp90isoforms pages 1-2, rios2024insightsintohsp90 pages 1-2)

Family/domain alignment: Hsp82 is a canonical Hsp90-family chaperone with N-terminal ATP-binding domain, middle (client interaction) domain, and C-terminal dimerization domain including the conserved co-chaperone-binding motif at the C-terminus. (backe2023saccharomycescerevisiaeas pages 17-22, rios2024insightsintohsp90 pages 2-3, girstmair2019thehsp90isoforms media 835ffb5d)

Conclusion: The literature examined is consistent with the UniProt-provided identity: ATP-dependent molecular chaperone Hsp82 (HSP82; yeast Hsp90 heat-inducible isoform) in S. cerevisiae.

1) Key concepts and definitions (current understanding)

1.1 What Hsp82 does (primary function)

Hsp82 (Hsp90) is an ATP-dependent molecular chaperone that assists the late-stage folding, activation, and stability of a large set of specific “client” proteins (substrates), including many signaling regulators (notably protein kinases and transcription factors). (mercier2023hsp90mutantswith pages 1-2, nathan1999identificationofssf1 pages 1-2)

Hsp90/Hsp82 is best understood as a proteostasis hub rather than a general chaperone for all misfolded proteins: it supports selective refolding/activation (e.g., luciferase) while leaving other proteins relatively unaffected in comparable assays. (rios2024insightsintohsp90 pages 3-5)

1.2 ATPase-coupled conformational cycle (mechanistic definition)

Yeast Hsp90 (Hsp82/Hsc82) is a dimeric chaperone cycling between:
- an open state (C-terminally dimerized) and
- an ATP-induced closed state with additional N-terminal contacts.

Client loading, conformational closing, ATP hydrolysis/nucleotide exchange, and reopening are regulated by co-chaperones that bind distinct surfaces and bias the timing of transitions. (rios2024insightsintohsp90 pages 2-3, mercier2023hsp90mutantswith pages 1-2)

A central current concept is that dwell time in specific conformations can be more functionally determinative than absolute ATPase rate, emphasizing kinetic regulation of the cycle in vivo. (backe2023saccharomycescerevisiaeas pages 3-4, mercier2023hsp90mutantswith pages 1-2)

1.3 Co-chaperones (key definitions)

Yeast has ~14 Hsp90 co-chaperones (diverse domain architectures) that target clients, modulate ATPase activity, and stabilize or destabilize conformational states:
- Sti1/Hop cooperates with Hsp70 to target clients to open Hsp90 and must be released for progression. (rios2024insightsintohsp90 pages 2-3)
- Sba1/p23 stabilizes closed states and can influence product release steps. (rios2024insightsintohsp90 pages 2-3)
- Aha1 stimulates ATP hydrolysis via the middle domain. (rios2024insightsintohsp90 pages 2-3)
- Cdc37 preferentially targets protein kinases. (rios2024insightsintohsp90 pages 2-3)

Recent yeast genetics has refined distinct roles of Hch1 (destabilizes Hsp90–nucleotide interaction and inhibits early-cycle progression) and Cpr6 (stabilizes the closed conformation and counterbalances Hch1), providing a more granular step-wise view of cochaperone regulation. (mercier2023hsp90mutantswith pages 1-2, rios2024insightsintohsp90 pages 3-5)

1.4 “Chaperone code” (PTM-based regulation)

A modern framing is that Hsp90 activity is tuned by a combined “chaperone code” of co-chaperone binding and post-translational modifications (PTMs), which can alter cochaperone affinity, ATPase activity, and client fate. (rios2024insightsintohsp90 pages 3-5, backe2023saccharomycescerevisiaeas pages 17-22)

2) Recent developments (prioritizing 2023–2024)

2.1 2024: Yeast-centered synthesis of mechanism and in vivo function

A 2024 review focused on S. cerevisiae consolidates key mechanistic insights: closed-state adoption is rate-limiting, cochaperones partition folding steps, and isoform differences (Hsp82 vs Hsc82) largely map to the N-terminal domain, shaping ATPase activity and inhibitor sensitivity. (rios2024insightsintohsp90 pages 2-3, rios2024insightsintohsp90 pages 1-2)

The same review provides a quantitative summary of induction: Hsp82 is very low at 25–30°C and induced at 37°C to levels similar to Hsc82, consistent with a stress-specialized role. (rios2024insightsintohsp90 pages 1-2)

2.2 2023: Mutant dissection reveals cochaperones as “conformational pacemakers”

In 2023, Mercier et al. used yeast Hsp90 mutants defective in distinct cycle steps (“loading/closing/reopening”) to show that cochaperone genetic interactions align with closed-state formation and that drug sensitivity correlates with the conformational step affected (e.g., loading-defective mutants most sensitive to an Hsp90 inhibitor). (mercier2023hsp90mutantswith pages 1-2)

2.3 2024: Quantitative proteomics maps cycle-dependent client pools

A 2024 DIA-MS study profiled soluble proteomes of yeast expressing wild-type Hsp90 or cycle mutants, providing quantitative evidence for client pool partitioning by conformational states and offering a platform for “selective inhibition” concepts.

The study measured 2,482 proteins (~38% of the yeast proteome) and detected 350 proteins (14%) with significant abundance changes (log2 FC ≥ 1.5); ~73% of the strongest-changed proteins had prior connections to Hsp90 function. (rios2024quantitativeproteomicanalysis pages 1-2)

3) Functional annotation narrative (processes, pathways, localization)

3.1 Biological processes and pathway roles

Essential proteostasis for selective signaling proteins: Classic yeast genetics and biochemistry established that the HSP82/HSC82 family is essential (double disruption lethal), and that Hsp90 supports key signaling regulators. (kimura1994temperaturesensitivemutantsof pages 1-2, chang1994conservationofhsp90 pages 1-2)

MAPK/pheromone signaling: Hsp90 is required for basal and pheromone-induced MAPK signaling, with Ste11 (yeast Raf-equivalent MAPKKK) identified as a key endogenous Hsp90 client/substrate required for accumulation and pathway function. (louvion1998hsp90isrequired pages 1-2)

Steroid receptor maturation (heterologous client assays): Multiple classic studies used glucocorticoid receptor (GR) and other steroid receptors expressed in yeast as sensitive Hsp90 readouts, demonstrating that Hsp90 keeps receptors in an activatable state and supports hormone-dependent activation. (louvion1998hsp90isrequired pages 1-2, kimura1994temperaturesensitivemutantsof pages 1-2)

3.2 Cellular localization and where Hsp82 acts

Primary localization: Cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth. (tapia2010hsp90nuclearaccumulation pages 1-2)

Condition-dependent nuclear accumulation: A key cell-biological finding is that Hsp90 (and the cochaperone Sba1/p23) accumulates in the nucleus in quiescent cells (glucose exhaustion) and in sporulating diploids; nuclear accumulation defects correlate with sporulation/spore-wall defects, and pharmacological inhibition (macbecin) similarly disrupts nuclear accumulation and spore development. (tapia2010hsp90nuclearaccumulation pages 1-2, tapia2010hsp90nuclearaccumulation pages 7-8)

4) Hsp82 vs Hsc82: specialization of two near-identical cytosolic isoforms

Multiple lines of evidence support that Hsp82 is tuned for stress conditions:
- Under nonstress conditions Hsc82 is ~10× more abundant; after heat shock Hsp82 is strongly induced so that levels become comparable. (girstmair2019thehsp90isoforms pages 1-2)
- Hsp82 is more thermally stable than Hsc82 (Tm ~60.4°C vs 57.1°C). (girstmair2019thehsp90isoforms pages 1-2, girstmair2019thehsp90isoforms media 00261b28)
- Hsc82 exhibits higher ATPase activity than Hsp82 at both 30°C and 37°C in comparative assays, and kinetic differences map largely to N-terminal-domain substitutions near the nucleotide pocket. (girstmair2019thehsp90isoforms pages 2-4, girstmair2019thehsp90isoforms pages 10-11, girstmair2019thehsp90isoforms media 7c8ac98c)

These findings support annotating Hsp82 as the heat-inducible, stress-resilient cytosolic Hsp90 isoform that preserves the core Hsp90 mechanism while shifting stability/dynamics. (girstmair2019thehsp90isoforms pages 1-2, rios2024insightsintohsp90 pages 1-2)

5) Applications and real-world implementations

5.1 Chemical-genetic screens and inhibitor studies in yeast

Yeast is widely used as a platform to probe Hsp90 mechanism and inhibitor response through drug sensitivity phenotypes and client reporters, and cross-species complementation (e.g., human Hsp90 isoforms expressed in yeast). (backe2023saccharomycescerevisiaeas pages 3-4, backe2023saccharomycescerevisiaeas pages 1-3)

A 2024 population-scale study explicitly used subtoxic Hsp90 inhibition as a screening proxy for environmental stress in growth/trait assays, demonstrating how Hsp90 perturbation can expose cryptic genetic variation and trait dependencies. (condic2024selectionforrobust pages 1-3, condic2024selectionforrobust pages 3-4)

5.2 Industrial fermentation and yeast domestication (2024 Science)

A 2024 Science study directly connects Hsp90 stress to economically important yeast traits: ethanol (a fermentation product) acts as a proteotoxic stressor that can compromise Hsp90-dependent regulators of sugar metabolism; domesticated beer and bread strains show increased robustness of maltose/maltotriose metabolism under Hsp90 stress, partly via gene duplications. (condic2024selectionforrobust pages 1-3, condic2024selectionforrobust pages 13-14)

In practical assay terms, the work demonstrates reproducible Hsp90 perturbation using radicicol at 4 μM and 10 μM, evaluated across 711 yeast strains and 12 metabolic traits. (condic2024selectionforrobust pages 1-3, condic2024selectionforrobust pages 3-4)

6) Quantitative summary table (recent statistics)

Finding/metric	Value(s)	Experimental context	Source (first author, year, journal)	URL	Notes for annotation
Hsp82 vs Hsc82 sequence identity	97% amino-acid identity; 16 residue differences	Comparative analysis of the two cytosolic yeast Hsp90 isoforms	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 1-2)	https://doi.org/10.1038/s41467-019-11518-w	Confirms HSP82 belongs to the Hsp90 family and is distinct from HSC82 despite very high similarity.
Hsp82 baseline abundance relative to Hsc82 under nonstress conditions	Hsc82 ~10-fold higher than Hsp82	Nonstress expression in S. cerevisiae	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 1-2)	https://doi.org/10.1038/s41467-019-11518-w	Supports annotation of Hsp82 as the low-baseline, stress-inducible cytosolic Hsp90 isoform.
Hsp82 induction at elevated temperature	At 37°C, Hsp82 rises to levels similar to Hsc82	Heat-induction of cytosolic Hsp90 isoforms	Rios, 2024, Frontiers in Molecular Biosciences (rios2024insightsintohsp90 pages 1-2)	https://doi.org/10.3389/fmolb.2024.1325590	Key evidence that HSP82 is the heat-inducible isoform.
Growth supported by reduced Hsp90 expression	1%–5% of wild-type expression still permits growth at optimal temperature, but not elevated temperature	Genetic expression reduction of yeast cytosolic Hsp90	Rios, 2024, Frontiers in Molecular Biosciences (rios2024insightsintohsp90 pages 1-2)	https://doi.org/10.3389/fmolb.2024.1325590	Indicates Hsp90 function is essential but quantitatively buffered under permissive conditions.
Essentiality of HSP82/HSC82 family	Single deletion viable; double disruption lethal	Classic yeast genetics of paralog pair	Kimura, 1994, Molecular and General Genetics (kimura1994temperaturesensitivemutantsof pages 1-2)	https://doi.org/10.1007/bf00285275	Important for functional annotation: at least one cytosolic Hsp90 isoform is required for viability.
Hsp82 melting temperature (Tm)	60.4 ± 0.5 °C	Thermal stability comparison without nucleotide	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 1-2)	https://doi.org/10.1038/s41467-019-11518-w	Reflects enhanced thermotolerance of Hsp82, consistent with stress specialization.
Hsc82 melting temperature (Tm)	57.1 ± 0.2 °C	Thermal stability comparison without nucleotide	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 1-2)	https://doi.org/10.1038/s41467-019-11518-w	Lower Tm than Hsp82 helps explain isoform specialization.
ATPγS effect on thermal stability	~+3 °C for both isoforms	ATP analog binding during thermal unfolding analysis	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 1-2)	https://doi.org/10.1038/s41467-019-11518-w	Supports ATP-dependent stabilization of the Hsp90 fold.
Hsc82 ATPase activity relative to Hsp82	~1.3-fold higher at 30°C; ~1.6-fold higher at 37°C	Isoform enzymology comparison	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 2-4)	https://doi.org/10.1038/s41467-019-11518-w	Indicates isoform-specific ATPase tuning rather than different core family assignment.
Hsp82 refolding efficiency vs Hsc82	~29% vs ~14% full refolding events	Single-molecule mechanical assays	Girstmair, 2019, Nature Communications (girstmair2019thehsp90isoforms pages 2-4)	https://doi.org/10.1038/s41467-019-11518-w	Quantifies superior resilience/refolding behavior of stress-induced Hsp82.
Proteome fraction broadly affected by Hsp90 inhibition	~10%–15% of proteins	Review of yeast Hsp90 functional impact	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Shows Hsp90 is selective but still proteome-broad in influence.
Proteomics dataset size	2,482 proteins measured (~38% of yeast proteome)	DIA-MS analysis of strains expressing wild-type or mutant Hsp90	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Useful benchmark for the scale of experimentally observed Hsp90-dependent proteome effects.
Proteins significantly altered in Hsp90 mutant dataset	350 proteins (14% of measured set), using log2 fold change ≥ 1.5	Quantitative proteomics of 9 Hsp90 mutants vs wild type	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Supports annotation of Hsp90/Hsp82 as a major proteostasis hub affecting many clients/indirect targets.
Previously known Hsp90-linked proteins within altered set	257/350 (~73%)	Cross-comparison of proteomic hits with prior Hsp90 literature	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Suggests many abundance changes reflect bona fide Hsp90-connected biology.
Number of Hsp90 mutants analyzed in proteomics study	9 mutants	Mutants disrupting distinct steps of the Hsp90 cycle	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Supports state-specific/client-specific functional annotation.
Principal component clustering of mutant effects	3 primary clusters	PCA of proteomic profiles from Hsp90-cycle mutants	Rios, 2024, Genetics (rios2024quantitativeproteomicanalysis pages 1-2)	https://doi.org/10.1093/genetics/iyae057	Suggests distinct conformational states support distinct client pools.
Industrial/domestication strain panel size	711 strains	Comparative analysis of domesticated and wild yeast robustness under Hsp90 stress	Condic, 2024, Science (condic2024selectionforrobust pages 1-3)	https://doi.org/10.1126/science.adi3048	Strong recent evidence linking Hsp90 to real-world fermentation adaptation.
Number of metabolic traits screened	12 traits	Hsp90 inhibition used as proxy for environmental/proteotoxic stress	Condic, 2024, Science (condic2024selectionforrobust pages 1-3)	https://doi.org/10.1126/science.adi3048	Demonstrates broad metabolic phenotyping framework for Hsp90-dependent robustness.
Radicicol concentrations used for Hsp90 perturbation	4 µM and 10 µM	Low and moderate Hsp90 disruption in chemical-genetic screens	Condic, 2024, Science (condic2024selectionforrobust pages 3-4)	https://doi.org/10.1126/science.adi3048	Practical concentrations for yeast Hsp90-stress screening assays.
Genetic variance in maltose robustness explained by MAL gene duplications	≥60% of genetic variance	Domestication/fermentation robustness under Hsp90 stress	Condic, 2024, Science (condic2024selectionforrobust pages 13-14)	https://doi.org/10.1126/science.adi3048	Indicates Hsp90-buffered variation has major quantitative consequences for industrial traits.
Diversity sampled in domestication analysis	73 genetic backgrounds; 10 ecological niches	Population-scale metabolic robustness analysis	Condic, 2024, Science (condic2024selectionforrobust pages 3-4)	https://doi.org/10.1126/science.adi3048	Shows the Hsp90 effect was evaluated across broad yeast diversity.
Statistical significance for trait variability across isolates	F test, P = 2.0585 × 10^-8	Variation in Hsp90-stress sensitivity across strains/traits	Condic, 2024, Science (condic2024selectionforrobust pages 3-4)	https://doi.org/10.1126/science.adi3048	Supports that Hsp90-dependent metabolic robustness differences are highly significant.
Hsp90 abundance can be reduced without viability at 25°C	~10-fold reduction tolerated at 25°C	Classic Hsp90 abundance/viability genetics	Nathan, 1999, PNAS (nathan1999identificationofssf1 pages 1-2)	https://doi.org/10.1073/pnas.96.4.1409	Reinforces the idea that abundance reserve exists under permissive conditions, despite essentiality of the family.

Table: This table compiles key numeric findings relevant to functional annotation of yeast HSP82/Hsp90, including isoform identity, heat induction, essentiality thresholds, thermal and ATPase differences, proteome-wide effects, and recent industrial screening data.

7) Visual evidence (domain architecture and isoform comparison)

The following images from Girstmair et al. (2019) provide visual support for the canonical Hsp90 domain architecture and quantitative isoform comparison tables (thermal stability, ATPase/inhibitor binding): (girstmair2019thehsp90isoforms media 835ffb5d, girstmair2019thehsp90isoforms media 00261b28, girstmair2019thehsp90isoforms media 7c8ac98c)

8) Practical functional-annotation statements (evidence-backed)

Gene product: ATP-dependent molecular chaperone (Hsp90 family), cytosolic, heat-inducible isoform. (rios2024insightsintohsp90 pages 1-2, girstmair2019thehsp90isoforms media 835ffb5d)

Molecular function: ATP binding and ATPase-coupled conformational cycling that supports folding/activation/stabilization of select client proteins (notably kinases and transcription factors), coordinated by cochaperones. (rios2024insightsintohsp90 pages 2-3, mercier2023hsp90mutantswith pages 1-2)

Biological process: Proteostasis and regulation of signaling networks; essentiality at organismal level arises from dependence of key clients/pathways (e.g., MAPK pheromone pathway via Ste11). (louvion1998hsp90isrequired pages 1-2, kimura1994temperaturesensitivemutantsof pages 1-2)

Cellular component: Cytosol under vegetative growth; condition-dependent nuclear accumulation during quiescence/sporulation. (tapia2010hsp90nuclearaccumulation pages 1-2)

9) Notes on evidence limitations

Some requested details (e.g., yeast-specific inhibitor IC50 values, or a direct paper snippet explicitly stating the systematic locus name YPL240C) were not present in the extracted full-text evidence corpus used here; however, UniProt mapping to P02829 and the yeast isoform context are explicitly supported by recent review literature, and functional/locus context is supported by multiple classic and modern yeast studies. (rios2024insightsintohsp90 pages 1-2, kimura1994temperaturesensitivemutantsof pages 1-2)

References

(rios2024insightsintohsp90 pages 1-2): Erick I. Rios, Isabel L. Hunsberger, and Jill L. Johnson. Insights into hsp90 mechanism and in vivo functions learned from studies in the yeast, saccharomyces cerevisiae. Frontiers in Molecular Biosciences, Feb 2024. URL: https://doi.org/10.3389/fmolb.2024.1325590, doi:10.3389/fmolb.2024.1325590. This article has 8 citations.
(girstmair2019thehsp90isoforms pages 1-2): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(backe2023saccharomycescerevisiaeas pages 17-22): Sarah J. Backe, Mehdi Mollapour, and Mark R. Woodford. saccharomyces cerevisiae as a tool for deciphering hsp90 molecular chaperone function. Essays in Biochemistry, 67:781-795, Sep 2023. URL: https://doi.org/10.1042/ebc20220224, doi:10.1042/ebc20220224. This article has 5 citations and is from a peer-reviewed journal.
(rios2024insightsintohsp90 pages 2-3): Erick I. Rios, Isabel L. Hunsberger, and Jill L. Johnson. Insights into hsp90 mechanism and in vivo functions learned from studies in the yeast, saccharomyces cerevisiae. Frontiers in Molecular Biosciences, Feb 2024. URL: https://doi.org/10.3389/fmolb.2024.1325590, doi:10.3389/fmolb.2024.1325590. This article has 8 citations.
(girstmair2019thehsp90isoforms media 835ffb5d): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(mercier2023hsp90mutantswith pages 1-2): Rebecca Mercier, Danielle Yama, Paul LaPointe, and Jill L. Johnson. Hsp90 mutants with distinct defects provide novel insights into cochaperone regulation of the folding cycle. PLOS Genetics, 19:e1010772, May 2023. URL: https://doi.org/10.1371/journal.pgen.1010772, doi:10.1371/journal.pgen.1010772. This article has 14 citations and is from a domain leading peer-reviewed journal.
(nathan1999identificationofssf1 pages 1-2): Debra F. Nathan, Melissa Harju Vos, and Susan Lindquist. Identification of ssf1, cns1, and hch1 as multicopy suppressors of a saccharomyces cerevisiae hsp90 loss-of-function mutation. Proceedings of the National Academy of Sciences of the United States of America, 96 4:1409-14, Feb 1999. URL: https://doi.org/10.1073/pnas.96.4.1409, doi:10.1073/pnas.96.4.1409. This article has 133 citations and is from a highest quality peer-reviewed journal.
(rios2024insightsintohsp90 pages 3-5): Erick I. Rios, Isabel L. Hunsberger, and Jill L. Johnson. Insights into hsp90 mechanism and in vivo functions learned from studies in the yeast, saccharomyces cerevisiae. Frontiers in Molecular Biosciences, Feb 2024. URL: https://doi.org/10.3389/fmolb.2024.1325590, doi:10.3389/fmolb.2024.1325590. This article has 8 citations.
(backe2023saccharomycescerevisiaeas pages 3-4): Sarah J. Backe, Mehdi Mollapour, and Mark R. Woodford. saccharomyces cerevisiae as a tool for deciphering hsp90 molecular chaperone function. Essays in Biochemistry, 67:781-795, Sep 2023. URL: https://doi.org/10.1042/ebc20220224, doi:10.1042/ebc20220224. This article has 5 citations and is from a peer-reviewed journal.
(rios2024quantitativeproteomicanalysis pages 1-2): Erick I Rios, Davi Gonçalves, Kevin A Morano, and Jill L Johnson. Quantitative proteomic analysis reveals unique hsp90 cycle-dependent client interactions. Genetics, Apr 2024. URL: https://doi.org/10.1093/genetics/iyae057, doi:10.1093/genetics/iyae057. This article has 5 citations and is from a domain leading peer-reviewed journal.
(kimura1994temperaturesensitivemutantsof pages 1-2): Yoko Kimura, Seiji Matsumoto, and Ichiro Yahara. Temperature-sensitive mutants of hsp82 of the budding yeast saccharomyces cerevisiae. Molecular and General Genetics MGG, 242:517-527, Mar 1994. URL: https://doi.org/10.1007/bf00285275, doi:10.1007/bf00285275. This article has 71 citations.
(chang1994conservationofhsp90 pages 1-2): H.C. Chang and S. Lindquist. Conservation of hsp90 macromolecular complexes in saccharomyces cerevisiae. Journal of Biological Chemistry, 269:24983-24988, Oct 1994. URL: https://doi.org/10.1016/s0021-9258(17)31486-2, doi:10.1016/s0021-9258(17)31486-2. This article has 219 citations and is from a domain leading peer-reviewed journal.
(louvion1998hsp90isrequired pages 1-2): Jean-François Louvion, Toufik Abbas-Terki, and Didier Picard. Hsp90 is required for pheromone signaling in yeast. Molecular biology of the cell, 9 11:3071-83, Nov 1998. URL: https://doi.org/10.1091/mbc.9.11.3071, doi:10.1091/mbc.9.11.3071. This article has 141 citations and is from a domain leading peer-reviewed journal.
(tapia2010hsp90nuclearaccumulation pages 1-2): Hugo Tapia and Kevin A. Morano. Hsp90 nuclear accumulation in quiescence is linked to chaperone function and spore development in yeast. Molecular Biology of the Cell, 21:63-72, Jan 2010. URL: https://doi.org/10.1091/mbc.e09-05-0376, doi:10.1091/mbc.e09-05-0376. This article has 54 citations and is from a domain leading peer-reviewed journal.
(tapia2010hsp90nuclearaccumulation pages 7-8): Hugo Tapia and Kevin A. Morano. Hsp90 nuclear accumulation in quiescence is linked to chaperone function and spore development in yeast. Molecular Biology of the Cell, 21:63-72, Jan 2010. URL: https://doi.org/10.1091/mbc.e09-05-0376, doi:10.1091/mbc.e09-05-0376. This article has 54 citations and is from a domain leading peer-reviewed journal.
(girstmair2019thehsp90isoforms media 00261b28): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(girstmair2019thehsp90isoforms pages 2-4): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(girstmair2019thehsp90isoforms pages 10-11): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(girstmair2019thehsp90isoforms media 7c8ac98c): Hannah Girstmair, Franziska Tippel, Abraham Lopez, Katarzyna Tych, Frank Stein, Per Haberkant, Philipp Werner Norbert Schmid, Dominic Helm, Matthias Rief, Michael Sattler, and Johannes Buchner. The hsp90 isoforms from s. cerevisiae differ in structure, function and client range. Nature Communications, Aug 2019. URL: https://doi.org/10.1038/s41467-019-11518-w, doi:10.1038/s41467-019-11518-w. This article has 84 citations and is from a highest quality peer-reviewed journal.
(backe2023saccharomycescerevisiaeas pages 1-3): Sarah J. Backe, Mehdi Mollapour, and Mark R. Woodford. saccharomyces cerevisiae as a tool for deciphering hsp90 molecular chaperone function. Essays in Biochemistry, 67:781-795, Sep 2023. URL: https://doi.org/10.1042/ebc20220224, doi:10.1042/ebc20220224. This article has 5 citations and is from a peer-reviewed journal.
(condic2024selectionforrobust pages 1-3): Natalia Condic, Hatim Amiji, Dipak Patel, William Charles Shropshire, Nejla Ozirmak Lermi, Youssef Sabha, Beryl John, Blake Hanson, and Georgios Ioannis Karras. Selection for robust metabolism in domesticated yeasts is driven by adaptation to hsp90 stress. Science, Jul 2024. URL: https://doi.org/10.1126/science.adi3048, doi:10.1126/science.adi3048. This article has 19 citations and is from a highest quality peer-reviewed journal.
(condic2024selectionforrobust pages 3-4): Natalia Condic, Hatim Amiji, Dipak Patel, William Charles Shropshire, Nejla Ozirmak Lermi, Youssef Sabha, Beryl John, Blake Hanson, and Georgios Ioannis Karras. Selection for robust metabolism in domesticated yeasts is driven by adaptation to hsp90 stress. Science, Jul 2024. URL: https://doi.org/10.1126/science.adi3048, doi:10.1126/science.adi3048. This article has 19 citations and is from a highest quality peer-reviewed journal.
(condic2024selectionforrobust pages 13-14): Natalia Condic, Hatim Amiji, Dipak Patel, William Charles Shropshire, Nejla Ozirmak Lermi, Youssef Sabha, Beryl John, Blake Hanson, and Georgios Ioannis Karras. Selection for robust metabolism in domesticated yeasts is driven by adaptation to hsp90 stress. Science, Jul 2024. URL: https://doi.org/10.1126/science.adi3048, doi:10.1126/science.adi3048. This article has 19 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

rios2024quantitativeproteomicanalysis pages 1-2
kimura1994temperaturesensitivemutantsof pages 1-2
condic2024selectionforrobust pages 1-3
condic2024selectionforrobust pages 3-4
condic2024selectionforrobust pages 13-14
backe2023saccharomycescerevisiaeas pages 17-22
backe2023saccharomycescerevisiaeas pages 3-4
backe2023saccharomycescerevisiaeas pages 1-3
https://doi.org/10.1038/s41467-019-11518-w
https://doi.org/10.3389/fmolb.2024.1325590
https://doi.org/10.1007/bf00285275
https://doi.org/10.1093/genetics/iyae057
https://doi.org/10.1126/science.adi3048
https://doi.org/10.1073/pnas.96.4.1409
https://doi.org/10.3389/fmolb.2024.1325590,
https://doi.org/10.1038/s41467-019-11518-w,
https://doi.org/10.1042/ebc20220224,
https://doi.org/10.1371/journal.pgen.1010772,
https://doi.org/10.1073/pnas.96.4.1409,
https://doi.org/10.1093/genetics/iyae057,
https://doi.org/10.1007/bf00285275,
https://doi.org/10.1016/s0021-9258(17
https://doi.org/10.1091/mbc.9.11.3071,
https://doi.org/10.1091/mbc.e09-05-0376,
https://doi.org/10.1126/science.adi3048,

📄 View Raw YAML

id: P02829
gene_symbol: HSP82
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  HSP82 is the stress-inducible isoform of Hsp90 in S. cerevisiae (the paralog of the constitutive Hsc82,
  with which it shares ~97% amino-acid identity). It is an ATP-dependent molecular chaperone
  that promotes the maturation, structural maintenance, and proper regulation of specific client proteins,
  particularly those involved in cell cycle control and signal transduction (e.g., the MAPKKK Ste11 in the
  pheromone/MAPK pathway). HSP82 functions as a homodimer,
  undergoing an ATP-dependent conformational cycle (open/closed transition) that acts as a molecular clamp on
  client proteins. It interacts with a large network of co-chaperones (STI1, AHA1, CDC37, SBA1, CPR6, CPR7,
  CNS1, SSE1, HCH1) that modulate its ATPase cycle and substrate recognition. Rather than a general chaperone
  for all misfolded proteins, Hsp82 acts as a selective proteostasis hub supporting late-stage folding,
  activation, and stability of a defined client set. HSP82 is induced by heat (very low at 25-30C, rising at
  37C to levels comparable to Hsc82) and is more thermally stable than Hsc82, and is required for growth at
  high temperatures. It is predominantly cytosolic during vegetative growth, with condition-dependent nuclear
  accumulation during quiescence and sporulation.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82/Hsp90 is a well-established protein folding chaperone. IBA annotation is consistent with the
      known function of this conserved chaperone family across eukaryotes. Falcon deep research frames Hsp82
      as a selective proteostasis hub that assists late-stage folding, activation, and stability of specific
      client proteins rather than acting as a general chaperone for all misfolded proteins.
    action: ACCEPT
    reason: >-
      Protein folding is a core biological process for Hsp90. UniProt describes HSP82 as a "Molecular chaperone
      that promotes the maturation, structural maintenance and proper regulation of specific target proteins."
      Multiple IMP and IDA evidence codes confirm involvement in de novo protein folding (PMID:10564510, PMID:9371781).
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsp82 (Hsp90) is an **ATP-dependent molecular chaperone** that assists the **late-stage folding,
        activation, and stability** of a large set of specific
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsp90/Hsp82 is best understood as a **proteostasis hub** rather than a general chaperone for all
        misfolded proteins
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 has well-characterized ATPase activity essential for its chaperone cycle. IBA annotation is correct.
      Falcon deep research places ATP hydrolysis within the dimeric open/closed conformational cycle, noting that
      the constitutive paralog Hsc82 has somewhat higher ATPase activity than Hsp82 (~1.3-fold at 30C, ~1.6-fold
      at 37C), with kinetic differences mapping to N-terminal-domain substitutions near the nucleotide pocket.
    action: ACCEPT
    reason: >-
      ATPase activity is fundamental to Hsp90 function. Directly demonstrated by IDA (PMID:12235160) and
      multiple structural studies showing ATP binding and hydrolysis. UniProt documents extensive mutagenesis
      data affecting ATPase activity (e.g., A41V causes 98% reduction, G83D abolishes activity).
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Client loading, conformational closing, ATP hydrolysis/nucleotide exchange, and reopening are
        **regulated by co-chaperones** that bind distinct surfaces and bias the timing of transitions
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsc82 exhibits **higher ATPase activity** than Hsp82 at both 30°C and 37°C in comparative assays, and
        kinetic differences map largely to N-terminal-domain substitutions near the nucleotide pocket
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 functions as a homodimer and forms complexes with many co-chaperones and client proteins.
      Falcon deep research notes that yeast has roughly 14 Hsp90 co-chaperones with diverse domain
      architectures that target clients, modulate ATPase activity, and stabilize or destabilize
      conformational states.
    action: ACCEPT
    reason: >-
      HSP82 is a homodimer and forms well-characterized complexes with co-chaperones (STI1, AHA1, SBA1, CDC37,
      CPR6, CPR7, CNS1, SSE1). Crystal structure of HSP82-SBA1-ATP closed complex (PDB:2CG9, PMID:16625188)
      confirms complex formation. ComplexPortal entry CPX-1276 (HMC complex) is documented.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Yeast has ~14 Hsp90 co-chaperones (diverse domain architectures) that **target clients**, **modulate
        ATPase activity**, and **stabilize or destabilize** conformational states
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for plasma membrane localization of HSP82. While Hsp90 is primarily cytoplasmic,
      some evidence exists for plasma membrane association in other organisms.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP82 is primarily cytoplasmic (IDA PMID:32920053, PMID:27385335). Plasma membrane localization
      is not well-established for the yeast protein specifically, but the IBA inference from orthologs
      is plausible for a minor pool. Not a core localization.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 binds ATP as part of its chaperone cycle. Well-established by crystallography.
    action: ACCEPT
    reason: >-
      ATP binding is essential for Hsp90 function. Multiple crystal structures show ATP/ADP binding
      (PDB:1AM1, 1AMW, 2CG9). UniProt documents extensive ATP binding site residues. The functional
      cycle is linked to ATP binding and hydrolysis.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 is a cytosolic protein. IBA annotation is correct. Falcon deep research confirms that cytosolic
      Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence for cytoplasm localization (PMID:32920053, PMID:27385335) and
      HDA data (PMID:11914276, PMID:14562095). Cytosol is the expected localization for Hsp90.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 stabilizes client proteins as part of its chaperone function. IBA annotation is appropriate.
      Falcon deep research describes Hsp82 as assisting the late-stage folding, activation, and stability
      of a defined set of client proteins.
    action: ACCEPT
    reason: >-
      Protein stabilization is a core function of Hsp90. IMP evidence shows HSP82 is required for
      protein maturation (PMID:27068472). UniProt states it "promotes the maturation, structural
      maintenance and proper regulation of specific target proteins."
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsp82 (Hsp90) is an **ATP-dependent molecular chaperone** that assists the **late-stage folding,
        activation, and stability** of a large set of specific
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP82 is the heat-inducible Hsp90 isoform, centrally involved in heat stress response. Falcon deep
      research provides quantitative support: Hsp82 is very low at 25-30C and induced at 37C to levels
      similar to the constitutive Hsc82 paralog, and Hsp82 is more thermally stable than Hsc82
      (Tm ~60.4C vs 57.1C), consistent with a stress-specialized role.
    action: ACCEPT
    reason: >-
      HSP82 is named as a heat shock protein precisely because it is induced by heat stress. UniProt
      confirms it is "required for growth at high temperatures" (PMID:2674684). The gene name itself
      (HSP82 = Heat Shock Protein 82) reflects this core function.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        **Hsp82 is very low at 25–30°C and induced at 37°C to levels similar to Hsc82**, consistent with a
        stress-specialized role
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsp82 is **more thermally stable** than Hsc82 (Tm ~60.4°C vs 57.1°C)
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 is proposed for obsoletion. HSP82 does interact with unfolded/misfolded client proteins
      but its mechanism is better captured by GO:0140662 (ATP-dependent protein folding chaperone).
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. HSP82 is an ATP-dependent foldase; while it does bind
      unfolded/non-native proteins as part of its chaperone cycle, the binding is coupled to ATP-driven
      conformational changes. The more appropriate term is GO:0140662 "ATP-dependent protein folding
      chaperone" which captures both the binding and the active folding mechanism. IDA evidence
      from PMID:10564510 demonstrated binding to denatured substrates, but this is part of the broader
      chaperone activity.
    proposed_replacement_terms:
    - id: GO:0140662
      label: ATP-dependent protein folding chaperone
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for perinuclear localization. HSP82 is primarily cytoplasmic with some nuclear
      presence; perinuclear enrichment is plausible from ortholog data.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP82 is found in both cytoplasm and nucleus (IDA PMID:32920053). Perinuclear localization
      is inferred from orthologs and may represent a minor pool. Not a primary localization.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping. Broader than ATP binding but not incorrect.
    action: ACCEPT
    reason: >-
      Nucleotide binding is a parent term of ATP binding. While more specific IBA and IEA annotations
      for ATP binding exist, this broader IEA annotation is not incorrect and reflects the UniProt
      keyword mapping. It is redundant with the more specific ATP binding annotation but acceptable.
- term:
    id: GO:0000492
    label: box C/D snoRNP assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA machine learning prediction for snoRNP assembly involvement. Supported by IMP evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by IMP evidence (PMID:18268103) which showed Hsp90 stabilizes Pih1/Nop17 to maintain
      R2TP complex activity that regulates snoRNA accumulation. This is a legitimate but secondary
      function of Hsp90, mediated through its general chaperone role on client proteins in the R2TP
      pathway.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ATP binding from InterPro/ARBA. Consistent with IBA and experimental evidence.
    action: ACCEPT
    reason: >-
      Redundant with IBA annotation but correct. ATP binding is a core molecular function of HSP82.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for cytoplasm from UniProt subcellular location mapping. Correct.
    action: ACCEPT
    reason: >-
      Consistent with multiple IDA and HDA evidence for cytoplasmic localization.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for protein folding. Redundant with IBA but correct.
    action: ACCEPT
    reason: >-
      Consistent with IBA and experimental annotations for protein folding involvement.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ATP hydrolysis activity. Redundant with IBA and IDA but correct.
    action: ACCEPT
    reason: >-
      Consistent with IBA and IDA (PMID:12235160) annotations for ATPase activity.
- term:
    id: GO:0043248
    label: proteasome assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA prediction for proteasome assembly involvement. Supported by IDA/IMP evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by experimental evidence (IDA and IMP, PMID:12853471). HSP82 assists in proteasome
      assembly as one of its client-dependent functions. Not a core function of HSP82 per se, but
      a legitimate downstream consequence of its chaperone activity.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for unfolded protein binding. Same issue as IBA annotation - term proposed for obsoletion.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. Should be replaced with GO:0140662 "ATP-dependent
      protein folding chaperone" which better captures the active chaperone mechanism.
    proposed_replacement_terms:
    - id: GO:0140662
      label: ATP-dependent protein folding chaperone
- term:
    id: GO:0140662
    label: ATP-dependent protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro for ATP-dependent protein folding chaperone. This is the correct
      and most informative molecular function term for HSP82. Falcon deep research describes Hsp82 as a
      dimeric chaperone cycling between an open (C-terminally dimerized) state and an ATP-induced closed
      state with additional N-terminal contacts.
    action: ACCEPT
    reason: >-
      GO:0140662 is the ideal molecular function term for HSP82/Hsp90. It captures both the ATP
      dependence and the protein folding chaperone activity. HSP82 binds to client proteins and
      assists their folding through an ATP-dependent conformational cycle. This should be considered
      the primary MF annotation for HSP82.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Yeast Hsp90 (Hsp82/Hsc82) is a **dimeric** chaperone cycling between
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        an **ATP-induced closed** state with additional N-terminal contacts
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11805837
  review:
    summary: >-
      IPI from large-scale mass spectrometry study. Uninformative "protein binding" annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative for a molecular chaperone that by definition binds many
      proteins. HSP82 interacts with dozens of co-chaperones and client proteins. The more informative
      annotation is GO:0140662 (ATP-dependent protein folding chaperone). Large-scale interaction
      studies produce many IPI annotations that do not capture specific molecular functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12604615
  review:
    summary: >-
      IPI from study of Aha1 binding to Hsp90. Specific interaction with co-chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While the interaction with Aha1 is genuine and important for the chaperone cycle, "protein binding"
      is uninformative. The chaperone function is better captured by GO:0140662.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14729968
  review:
    summary: >-
      IPI from ctf13/RSC study. Generic protein binding annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15102838
  review:
    summary: >-
      IPI from Hap1 interaction study. HSP82 interacts with the transcription factor Hap1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While HSP82-Hap1 interaction is genuine, "protein binding" is uninformative for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15766533
  review:
    summary: >-
      IPI from large-scale chaperone network study (Zhao et al 2005). Many interactions detected.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale study detecting many chaperone-client and chaperone-cochaperone interactions. "Protein
      binding" is uninformative for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15879519
  review:
    summary: >-
      IPI from yeast two-hybrid screen for Hsp90 interactors.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone with extensive interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16407978
  review:
    summary: >-
      IPI from Ppt1 phosphatase study. Ppt1 is a dedicated regulator of Hsp90.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16429126
  review:
    summary: >-
      IPI from proteome survey.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554755
  review:
    summary: >-
      IPI from large-scale protein complex study (Krogan et al 2006).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16625188
  review:
    summary: >-
      IPI from crystal structure of HSP82-SBA1-nucleotide complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While the SBA1 interaction is structurally characterized, "protein binding" is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18268103
  review:
    summary: >-
      IPI from R2TP complex/snoRNP assembly study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18719252
  review:
    summary: >-
      IPI from high-quality binary interaction map.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18818696
  review:
    summary: >-
      IPI from Sgt1 complex study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18833289
  review:
    summary: >-
      IPI from protein interaction study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19536198
  review:
    summary: >-
      IPI from atlas of chaperone-protein interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone. This study itself maps the chaperone interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21170051
  review:
    summary: >-
      IPI from mixed Hsp90-cochaperone complex study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21734642
  review:
    summary: >-
      IPI from SAGA/ADA complex study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21892170
  review:
    summary: >-
      IPI from structural analysis of Hsp90-p53 interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23217712
  review:
    summary: >-
      IPI from CDK-dependent Hsp70 phosphorylation study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23396352
  review:
    summary: >-
      IPI from Aha1 integration into Hsp90 co-chaperone cycle study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24012479
  review:
    summary: >-
      IPI from protein interaction study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24794838
  review:
    summary: >-
      IPI from Tel2-Hsp90-Pih1 structural study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31454312
  review:
    summary: >-
      IPI from structural pleiotropy study of Hsp90 paralogs.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37968396
  review:
    summary: >-
      IPI from yeast protein interactome architecture study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9817749
  review:
    summary: >-
      IPI from study showing Hsp90 function depends on ATP binding and hydrolysis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone. The actual finding is about
      ATP-dependent chaperone function, not generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9819422
  review:
    summary: >-
      IPI from Cns1/CPR7 interaction study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" for a chaperone.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16625188
  review:
    summary: >-
      HSP82 forms homodimers as part of its functional cycle. The crystal structure (PDB:2CG9)
      confirms dimerization. Falcon deep research describes yeast Hsp90 as a dimeric chaperone whose
      open state is C-terminally dimerized, with the conserved co-chaperone-binding motif at the C-terminus.
    action: ACCEPT
    reason: >-
      Homodimerization is essential for Hsp90 function. The crystal structure of the closed chaperone
      complex (PMID:16625188) directly shows the dimer. This is a core structural feature of Hsp90.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        an **open** state (C-terminally dimerized) and
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        **C-terminal dimerization domain** including the conserved co-chaperone-binding motif at the
        C-terminus
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18268103
  review:
    summary: >-
      Additional evidence for HSP82 homodimerization.
    action: ACCEPT
    reason: >-
      Consistent with known Hsp90 dimerization. Duplicate annotation with different reference is fine.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19696785
  review:
    summary: >-
      HSP82 homodimerization via C-terminal domain switch point study.
    action: ACCEPT
    reason: >-
      C-terminal domain dimerization dynamics are important for the conformational cycle.
      Mutagenesis of A577 modulates dimerization, ATPase, and client activation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20736353
  review:
    summary: >-
      HSP82 C-terminal dimerization dynamics study.
    action: ACCEPT
    reason: >-
      Further confirmation of homodimerization as essential for the conformational cycle.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23396352
  review:
    summary: >-
      HSP82 homodimerization in context of Aha1 co-chaperone cycle.
    action: ACCEPT
    reason: >-
      Consistent with known Hsp90 dimerization.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24794838
  review:
    summary: >-
      HSP82 homodimerization in Tel2-Hsp90-Pih1 study.
    action: ACCEPT
    reason: >-
      Consistent with known Hsp90 dimerization.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31454312
  review:
    summary: >-
      HSP82 homodimerization in paralog heteromer study.
    action: ACCEPT
    reason: >-
      Consistent with known Hsp90 dimerization and also documents HSP82-HSC82 heterodimerization.
- term:
    id: GO:0070482
    label: response to oxygen levels
  evidence_type: NAS
  original_reference_id: PMID:9632766
  review:
    summary: >-
      NAS annotation from ComplexPortal, based on HSP82 involvement in HAP1-mediated heme signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP82 forms a complex with HAP1, a transcriptional activator regulated by heme (proxy for
      oxygen). This is a client-dependent function. The NAS evidence is weak but the underlying
      biology is supported by UniProt documentation of HSP82-HAP1 interaction (PMID:9632766).
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:32920053
  review:
    summary: >-
      IDA evidence for nuclear localization from starvation phosphorylation study. Falcon deep research
      reinforces a condition-dependent nuclear pool: Hsp90 (with the co-chaperone Sba1/p23) accumulates in
      the nucleus in quiescent cells (glucose exhaustion) and in sporulating diploids, where nuclear
      accumulation defects correlate with sporulation/spore-wall defects.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP82 is primarily cytoplasmic but a nuclear pool exists, enhanced during starvation, quiescence, and
      sporulation. The starvation study (PMID:32920053) showed phosphorylation-dependent nuclear localization,
      and falcon deep research corroborates condition-dependent nuclear accumulation (Tapia & Morano 2010).
      Nuclear localization remains a regulated, non-core compartment rather than the primary site of action.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        **accumulates in the nucleus in quiescent cells (glucose exhaustion)** and in sporulating diploids
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:32920053
  review:
    summary: >-
      IDA evidence for cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Core localization of HSP82. Consistent with multiple lines of evidence.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:12235160
  review:
    summary: >-
      Direct assay evidence for ATPase activity of HSP82.
    action: ACCEPT
    reason: >-
      Core molecular function. Direct biochemical measurement of ATPase activity.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IMP
  original_reference_id: PMID:27068472
  review:
    summary: >-
      Mutant phenotype evidence for ATPase activity from systematic mutant analysis.
    action: ACCEPT
    reason: >-
      Systematic mutant analysis showing ATPase activity is required for client-specific
      and general Hsp90 functions. Complements IDA evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:11914276
  review:
    summary: >-
      High-throughput data for cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:14562095
  review:
    summary: >-
      High-throughput GFP localization data confirming cytoplasm.
    action: ACCEPT
    reason: >-
      Global protein localization study. Consistent with IDA evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:27385335
  review:
    summary: >-
      IDA from split-GFP system at septin collar.
    action: ACCEPT
    reason: >-
      Consistent with cytoplasmic localization.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IMP
  original_reference_id: PMID:27068472
  review:
    summary: >-
      IMP evidence from systematic mutant analysis showing HSP82 is required for protein maturation.
    action: ACCEPT
    reason: >-
      UniProt describes HSP82 as promoting "the maturation, structural maintenance and proper regulation
      of specific target proteins." Protein maturation is a core function of Hsp90.
- term:
    id: GO:0000492
    label: box C/D snoRNP assembly
  evidence_type: IMP
  original_reference_id: PMID:18268103
  review:
    summary: >-
      IMP evidence showing Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex for snoRNP assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hsp90 acts on the R2TP pathway components (Pih1, Tah1) that are required for snoRNP assembly.
      This is a legitimate client-dependent function but not a core function of HSP82.
- term:
    id: GO:0006458
    label: "'de novo' protein folding"
  evidence_type: IDA
  original_reference_id: PMID:10564510
  review:
    summary: >-
      Direct assay evidence for de novo protein folding by HSP82. Falcon deep research emphasizes that this
      is selective: Hsp90/Hsp82 supports refolding/activation of specific substrates (e.g., luciferase)
      rather than acting as a general chaperone for all misfolded proteins.
    action: ACCEPT
    reason: >-
      Study of N- and C-terminal domain contributions to Hsp90 function in S. cerevisiae.
      Demonstrates involvement in de novo protein folding.
    additional_reference_ids:
    - file:yeast/HSP82/HSP82-deep-research-falcon.md
    supported_by:
    - reference_id: file:yeast/HSP82/HSP82-deep-research-falcon.md
      supporting_text: >-
        Hsp90/Hsp82 is best understood as a **proteostasis hub** rather than a general chaperone for all
        misfolded proteins
- term:
    id: GO:0006458
    label: "'de novo' protein folding"
  evidence_type: IMP
  original_reference_id: PMID:9371781
  review:
    summary: >-
      IMP evidence for de novo protein folding from in vivo function study.
    action: ACCEPT
    reason: >-
      Study of in vivo functions of Hsp90 in S. cerevisiae. Demonstrates role in de novo protein
      folding through mutant analysis.
- term:
    id: GO:0006970
    label: response to osmotic stress
  evidence_type: IMP
  original_reference_id: PMID:16487343
  review:
    summary: >-
      IMP evidence showing Hsp90 is required for high osmotic stress response.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hsp90 is required for the osmotic stress response, likely through chaperoning stress-responsive
      kinases (e.g., Hog1 pathway clients). This is a stress-responsive function but secondary to the
      core chaperone activity.
- term:
    id: GO:0032212
    label: positive regulation of telomere maintenance via telomerase
  evidence_type: IDA
  original_reference_id: PMID:17954556
  review:
    summary: >-
      IDA evidence for positive regulation of telomere maintenance via telomerase.
    action: KEEP_AS_NON_CORE
    reason: >-
      Hsp90 modulates multiple telomerase activities. This is a client-dependent function where
      Hsp90 chaperones telomerase components. Not a core function of HSP82 itself.
- term:
    id: GO:0032212
    label: positive regulation of telomere maintenance via telomerase
  evidence_type: IMP
  original_reference_id: PMID:17954556
  review:
    summary: >-
      IMP evidence for telomerase regulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Complements IDA evidence. Client-dependent function.
- term:
    id: GO:0042026
    label: protein refolding
  evidence_type: IMP
  original_reference_id: PMID:9371781
  review:
    summary: >-
      IMP evidence for protein refolding activity from in vivo function study.
    action: ACCEPT
    reason: >-
      Protein refolding is a core function of Hsp90. The in vivo study demonstrates this capacity.
- term:
    id: GO:0043248
    label: proteasome assembly
  evidence_type: IDA
  original_reference_id: PMID:12853471
  review:
    summary: >-
      IDA evidence for proteasome assembly involvement.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP82 assists in proteasome assembly as a client-dependent function. The chaperone assists
      proteasome maturation but this is secondary to its core function.
- term:
    id: GO:0043248
    label: proteasome assembly
  evidence_type: IMP
  original_reference_id: PMID:12853471
  review:
    summary: >-
      IMP evidence for proteasome assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      Complements IDA evidence. Client-dependent function.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10564510
  review:
    summary: >-
      IDA evidence showing HSP82 binds unfolded/denatured proteins. Term proposed for obsoletion.
    action: MODIFY
    reason: >-
      While the experimental evidence is solid (HSP82 does bind unfolded proteins as shown by
      PMID:10564510), GO:0051082 is proposed for obsoletion. The binding of unfolded proteins
      is part of the ATP-dependent chaperone mechanism, better captured by GO:0140662
      "ATP-dependent protein folding chaperone."
    proposed_replacement_terms:
    - id: GO:0140662
      label: ATP-dependent protein folding chaperone
- term:
    id: GO:0032204
    label: regulation of telomere maintenance
  evidence_type: IMP
  original_reference_id: PMID:21829731
  review:
    summary: >-
      IMP evidence from CACAO annotation showing HSP90 controls SIR2-mediated gene silencing
      and telomere maintenance.
    action: KEEP_AS_NON_CORE
    reason: >-
      HSP90 controls SIR2-mediated gene silencing which affects telomere maintenance. This is
      another example of a client-dependent function. Secondary to core chaperone activity.
core_functions:
- description: >-
    Primary molecular function: ATP-dependent protein folding chaperone. HSP82 binds to
    client proteins and assists their folding through an ATP-dependent conformational cycle.
    Supported by IEA from InterPro, IDA evidence for ATP hydrolysis (PMID:12235160), unfolded
    protein binding (PMID:10564510), and de novo protein folding (PMID:10564510). Crystal
    structures confirm ATP-dependent conformational cycle (PDB:2CG9).
  molecular_function:
    id: GO:0140662
    label: ATP-dependent protein folding chaperone
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  - id: GO:0034605
    label: cellular response to heat
  locations:
  - id: GO:0005737
    label: cytoplasm
- description: >-
    ATPase activity is fundamental to the Hsp90 chaperone cycle. Directly demonstrated by
    IDA (PMID:12235160) and IMP (PMID:27068472). Extensive mutagenesis data documents residues
    critical for ATPase activity.
  molecular_function:
    id: GO:0016887
    label: ATP hydrolysis activity
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005737
    label: cytoplasm
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
  - statement: Hsp82 is annotated to ATP-dependent protein folding chaperone (GO:0140662) and protein folding (GO:0006457) via InterPro-to-GO mapping reflecting Hsp90 family membership.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: PANTHER phylogenetic-tree annotation propagates conserved Hsp90 chaperone functions (ATP binding, ATP hydrolysis, protein folding, cellular response to heat, protein stabilization, identical protein binding, cytosol localization) to S. cerevisiae HSP82.
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: UniProtKB keyword 'Nucleotide-binding' maps to GO:0000166 nucleotide binding for HSP82 based on its conserved Hsp90 ATPase domain.
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings:
  - statement: HSP82 UniProt subcellular location annotation (cytoplasm) is mapped to GO:0005737 cytoplasm.
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings:
  - statement: ARBA machine-learning model assigns HSP82 to box C/D snoRNP assembly and proteasome assembly based on Hsp90 family signatures and chaperone client patterns.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: Combined automated IEA pipelines annotate HSP82 with ATP binding, ATP hydrolysis activity, protein folding, and unfolded protein binding from UniProt features.
- id: PMID:10564510
  title: Contribution of N- and C-terminal domains to the function of Hsp90 in Saccharomyces cerevisiae.
  findings:
  - statement: Direct evidence for de novo protein folding and unfolded protein binding by HSP82
    full_text_unavailable: true
- id: PMID:11805837
  title: Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry.
  findings:
  - statement: HSP82 was identified as part of multi-protein complexes in S. cerevisiae by systematic affinity purification-mass spectrometry; supports broad protein-binding annotations of HSP82 as a chaperone hub.
    full_text_unavailable: true
- id: PMID:11914276
  title: Subcellular localization of the yeast proteome.
  findings:
  - statement: Subcellular localization survey assigns HSP82 to the cytoplasm in S. cerevisiae, consistent with its predominant cytosolic chaperone role.
    full_text_unavailable: true
- id: PMID:12235160
  title: N-terminal residues regulate the catalytic efficiency of the Hsp90 ATPase cycle.
  findings:
  - statement: Direct biochemical assay of ATPase activity
    full_text_unavailable: true
- id: PMID:12604615
  title: Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone.
  findings:
  - statement: Aha1 binds the middle domain of Hsp90 (HSP82), stimulates ATPase activity, and contributes to client protein activation, anchoring HSP82 in the canonical Hsp90 co-chaperone cycle.
    full_text_unavailable: true
- id: PMID:12853471
  title: The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome.
  findings:
  - statement: HSP82/Hsp90 is required for assembly and maintenance of the 26S proteasome in vivo, supporting GO:0043248 proteasome assembly as a client-dependent secondary function.
    supporting_text: Functional loss of Hsp90 using a temperature-sensitive mutant in yeast caused dissociation of the 26S proteasome.
    reference_section_type: ABSTRACT
- id: PMID:14562095
  title: Global analysis of protein localization in budding yeast.
  findings:
  - statement: Genome-wide GFP localization study assigns HSP82 to the cytoplasm in S. cerevisiae.
    full_text_unavailable: true
- id: PMID:14729968
  title: The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion.
  findings:
  - statement: This paper supports the IPI annotation of HSP82 to protein binding (GO:0005515) but does not provide visible abstract-level evidence for HSP82 function; the IPI annotation is correctly flagged MARK_AS_OVER_ANNOTATED in this review.
    full_text_unavailable: true
- id: PMID:15102838
  title: 'A novel mode of chaperone action: heme activation of Hap1 by enhanced association of Hsp90 with the repressed Hsp70-Hap1 complex.'
  findings:
  - statement: HSP82/Hsp90 activates the heme-regulated transcription factor Hap1 by enhancing association with the repressed Hsp70-Hap1 complex; demonstrates client-specific chaperone action.
    full_text_unavailable: true
- id: PMID:15766533
  title: 'Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone.'
  findings:
  - statement: Integrative map of HSP82/Hsp90 physical and genetic interactions defines its central position in the yeast chaperone network.
    full_text_unavailable: true
- id: PMID:15879519
  title: "A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p)."
  findings:
  - statement: Yeast two-hybrid screen of the proteome identifies many HSP82/Hsp90 interactors, supporting its role as a chaperone hub.
    full_text_unavailable: true
- id: PMID:16407978
  title: The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90.
  findings:
  - statement: The phosphatase Ppt1 is a dedicated regulator of HSP82/Hsp90 chaperone activity, identifying a specific co-chaperone-like interaction.
    full_text_unavailable: true
- id: PMID:16429126
  title: Proteome survey reveals modularity of the yeast cell machinery.
  findings:
  - statement: Proteome survey of yeast cellular machinery places HSP82 within multi-protein modules consistent with its chaperone hub status.
    full_text_unavailable: true
- id: PMID:16487343
  title: The molecular chaperone Hsp90 is required for high osmotic stress response in Saccharomyces cerevisiae.
  findings:
  - statement: HSP82/Hsp90 is required for the high osmotic stress response in S. cerevisiae, supporting GO:0006970 response to osmotic stress as a client-dependent function.
    full_text_unavailable: true
- id: PMID:16554755
  title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
  findings:
  - statement: HSP82 is part of the global landscape of yeast protein complexes mapped by tandem affinity purification.
    full_text_unavailable: true
- id: PMID:16625188
  title: Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.
  findings:
  - statement: Crystal structure of full-length Hsp82 dimer in closed conformation with SBA1 and ATP
    supporting_text: Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1.
    reference_section_type: ABSTRACT
- id: PMID:17954556
  title: The hsp90 molecular chaperone modulates multiple telomerase activities.
  findings:
  - statement: HSP82/Hsp90 modulates multiple telomerase activities, supporting its role in positive regulation of telomere maintenance via telomerase as a client-dependent function.
    full_text_unavailable: true
- id: PMID:18268103
  title: Molecular chaperone Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation.
  findings:
  - statement: HSP82/Hsp90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation, providing IMP evidence for box C/D snoRNP assembly involvement.
    supporting_text: Together with the Tah1 cofactor, Hsp90 functions to stabilize Pih1. As a consequence, the chaperone is shown to affect box C/D accumulation and maintenance, especially under stress conditions.
    reference_section_type: ABSTRACT
- id: PMID:18719252
  title: High-quality binary protein interaction map of the yeast interactome network.
  findings:
  - statement: HSP82 is captured in a high-quality binary interaction map of the yeast interactome.
    full_text_unavailable: true
- id: PMID:18818696
  title: Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes.
  findings:
  - statement: Structural and functional studies couple HSP82/Hsp90 to Sgt1-centered multi-protein complexes (yeast-specific Sgt1-Hsp90 interaction), supporting its co-chaperone-mediated client recruitment.
    full_text_unavailable: true
- id: PMID:18833289
  title: Structural and functional analysis of SGT1-HSP90 core complex required for innate immunity in plants.
  findings:
  - statement: Plant SGT1-HSP90 structural/functional study; cited here for cross-species context on conserved Hsp90 chaperone-cochaperone scaffolding rather than direct yeast HSP82 evidence (yeast-specific Sgt1-Hsp90 interaction is documented in PMID:18818696).
    full_text_unavailable: true
- id: PMID:19536198
  title: 'An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell.'
  findings:
  - statement: Yeast atlas of chaperone-protein interactions defines HSP82's extensive chaperone-client and chaperone-cochaperone interaction network.
    full_text_unavailable: true
- id: PMID:19696785
  title: Hsp90 is regulated by a switch point in the C-terminal domain.
  findings:
  - statement: Hsp82 is regulated by a C-terminal switch-point that modulates dimerization, ATPase, and client activation; supports identical protein binding (homodimerization) annotations.
    full_text_unavailable: true
- id: PMID:20736353
  title: Dynamics of heat shock protein 90 C-terminal dimerization is an important part of its conformational cycle.
  findings:
  - statement: C-terminal dimerization dynamics of HSP82 are an integral part of its conformational cycle, providing additional support for homodimerization (GO:0042802).
    full_text_unavailable: true
- id: PMID:21170051
  title: Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle.
  findings:
  - statement: Mixed Hsp82-cochaperone complexes are important for progression of the chaperone reaction cycle, supporting integration of HSP82 in dynamic multi-protein assemblies.
    full_text_unavailable: true
- id: PMID:21734642
  title: Combinatorial depletion analysis to assemble the network architecture of the SAGA and ADA chromatin remodeling complexes.
  findings:
  - statement: HSP82 was detected in combinatorial depletion analyses assembling the SAGA/ADA chromatin remodeling complex network, consistent with broad interactome.
    full_text_unavailable: true
- id: PMID:21829731
  title: HSP90 controls SIR2 mediated gene silencing.
  findings:
  - statement: HSP90 controls SIR2-mediated gene silencing, supporting client-dependent regulation of telomere maintenance and chromatin silencing.
    full_text_unavailable: true
- id: PMID:21892170
  title: Structural analysis of the interaction between Hsp90 and the tumor suppressor protein p53.
  findings:
  - statement: Structural analysis of HSP82-p53 interaction characterizes a client-binding interface relevant to Hsp90's tumor-suppressor chaperone activity.
    full_text_unavailable: true
- id: PMID:23217712
  title: CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression.
  findings:
  - statement: CDK-dependent Hsp70 phosphorylation controls G1 cyclin abundance, with HSP82 contributing to cell-cycle progression via its co-chaperone partnership with Hsp70.
    full_text_unavailable: true
- id: PMID:23396352
  title: Integration of the accelerator Aha1 in the Hsp90 co-chaperone cycle.
  findings:
  - statement: Aha1 integrates as an accelerator of the HSP82/Hsp90 co-chaperone cycle, providing biochemical/structural support for ATPase regulation.
    full_text_unavailable: true
- id: PMID:24012479
  title: High-resolution structural analysis shows how Tah1 tethers Hsp90 to the R2TP complex.
  findings:
  - statement: High-resolution structural analysis shows that Tah1 tethers HSP82/Hsp90 to the R2TP complex, supporting client recruitment to snoRNP/RNA polymerase II-related assemblies.
    full_text_unavailable: true
- id: PMID:24794838
  title: Structural basis for phosphorylation-dependent recruitment of Tel2 to Hsp90 by Pih1.
  findings:
  - statement: Structural basis for phosphorylation-dependent recruitment of Tel2 to HSP82/Hsp90 by Pih1 supports HSP82's role in TTT-R2TP-mediated kinase chaperoning.
    full_text_unavailable: true
- id: PMID:27068472
  title: Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function.
  findings:
  - statement: Systematic mutant analysis of Hsp90 function
    full_text_unavailable: true
- id: PMID:27385335
  title: Detection of protein-protein interactions at the septin collar in Saccharomyces cerevisiae using a tripartite split-GFP system.
  findings:
  - statement: Tripartite split-GFP system places HSP82 at the septin collar in S. cerevisiae, supporting cytoplasmic localization with sub-cellular specificity.
    full_text_unavailable: true
- id: PMID:31454312
  title: The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs.
  findings:
  - statement: Structural pleiotropy and regulatory evolution maintain HSP82-HSC82 paralog heteromers, providing further support for identical protein binding (homo- and heterodimerization).
    full_text_unavailable: true
- id: PMID:32920053
  title: A Single Site Phosphorylation on Hsp82 Ensures Cell Survival during Starvation in Saccharomyces cerevisiae.
  findings:
  - statement: Single-site phosphorylation on HSP82 governs nuclear redistribution during starvation; supports both cytoplasmic and nuclear pools of HSP82.
    supporting_text: Ppt1 regulates Hsp82 distribution in the cytoplasm and nucleus by dephosphorylating the S485 residue on Hsp82.
    reference_section_type: ABSTRACT
- id: PMID:37968396
  title: The social and structural architecture of the yeast protein interactome.
  findings:
  - statement: HSP82 is part of the social/structural architecture of the yeast protein interactome captured by integrative network analysis.
    full_text_unavailable: true
- id: PMID:9371781
  title: In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone.
  findings:
  - statement: In vivo demonstration of protein folding and refolding functions
    supporting_text: The data suggest that Hsp90 is not required for the de novo folding of most proteins, but it is required for a specific subset of proteins that have greater difficulty reaching their native conformations.
    reference_section_type: ABSTRACT
- id: PMID:9632766
  title: 'Molecular mechanism governing heme signaling in yeast: a higher-order complex mediates heme regulation of the transcriptional activator HAP1.'
  findings:
  - statement: HSP82 forms a higher-order complex that mediates heme regulation of the transcriptional activator HAP1, supporting client-dependent response to oxygen levels.
    full_text_unavailable: true
- id: PMID:9817749
  title: In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis.
  findings:
  - statement: In vivo Hsp82 function is dependent on ATP binding and ATP hydrolysis, anchoring the ATPase cycle as essential for cellular chaperone activity.
    full_text_unavailable: true
- id: PMID:9819422
  title: Cns1 is an essential protein associated with the hsp90 chaperone complex in Saccharomyces cerevisiae that can restore cyclophilin 40-dependent functions in cpr7Delta cells.
  findings:
  - statement: Cns1 is an essential Hsp82-associated co-chaperone that can restore cyclophilin 40-dependent functions in cpr7Delta cells, supporting HSP82 cochaperone-network annotations.
    full_text_unavailable: true
- id: PMID:2674684
  title: hsp82 is an essential protein that is required in higher concentrations for growth of cells at higher temperatures.
  findings:
  - statement: HSP82 is essential and required at higher concentrations for growth at elevated temperatures
    full_text_unavailable: true
- id: file:yeast/HSP82/HSP82-deep-research-falcon.md
  title: Falcon deep research report on yeast HSP82 (Hsp90)
  findings:
  - statement: |
      Hsp82 is an ATP-dependent molecular chaperone that assists late-stage folding, activation,
      and stability of a defined set of specific client proteins, acting as a selective proteostasis
      hub rather than a general chaperone for all misfolded proteins.
    supporting_text: |-
      Hsp82 (Hsp90) is an **ATP-dependent molecular chaperone** that assists the **late-stage folding, activation, and stability** of a large set of specific “client” proteins (substrates), including many signaling regulators (notably protein kinases and transcription factors).
    reference_section_type: RESULTS
  - statement: |
      Yeast Hsp90 (Hsp82/Hsc82) is a dimeric chaperone cycling between an open, C-terminally
      dimerized state and an ATP-induced closed state with additional N-terminal contacts, regulated
      by co-chaperones.
    supporting_text: |-
      Yeast Hsp90 (Hsp82/Hsc82) is a **dimeric** chaperone cycling between:
      - an **open** state (C-terminally dimerized) and
      - an **ATP-induced closed** state with additional N-terminal contacts.
    reference_section_type: RESULTS
  - statement: |
      Yeast has approximately 14 Hsp90 co-chaperones that target clients, modulate ATPase activity,
      and stabilize or destabilize conformational states; Sti1/Hop targets clients to open Hsp90,
      Sba1/p23 stabilizes closed states, Aha1 stimulates ATP hydrolysis, and Cdc37 targets kinases.
    supporting_text: |-
      Yeast has ~14 Hsp90 co-chaperones (diverse domain architectures) that **target clients**, **modulate ATPase activity**, and **stabilize or destabilize** conformational states:
    reference_section_type: RESULTS
  - statement: |
      HSP82 is the heat-inducible cytosolic Hsp90 isoform: very low at 25-30C and induced at 37C to
      levels similar to the constitutive Hsc82, consistent with a stress-specialized role.
    supporting_text: |-
      **Hsp82 is very low at 25–30°C and induced at 37°C to levels similar to Hsc82**, consistent with a stress-specialized role.
    reference_section_type: RESULTS
  - statement: |
      Hsp82 is more thermally stable than Hsc82 (Tm ~60.4C vs 57.1C) and shows superior refolding
      (~29% vs ~14% full refolding events in single-molecule assays), while Hsc82 has somewhat
      higher ATPase activity, reflecting isoform specialization mapping to the N-terminal domain.
    supporting_text: |-
      Hsp82 is **more thermally stable** than Hsc82 (Tm ~60.4°C vs 57.1°C). (girstmair2019thehsp90isoforms pages 1-2, girstmair2019thehsp90isoforms media 00261b28)
    reference_section_type: RESULTS
  - statement: |
      Hsp90 is required for basal and pheromone-induced MAPK signaling in yeast, with Ste11
      (the yeast Raf-equivalent MAPKKK) identified as a key endogenous client/substrate required
      for pathway accumulation and function.
    supporting_text: |-
      **MAPK/pheromone signaling:** Hsp90 is required for basal and pheromone-induced MAPK signaling, with **Ste11 (yeast Raf-equivalent MAPKKK)** identified as a key endogenous Hsp90 client/substrate required for accumulation and pathway function.
    reference_section_type: RESULTS
  - statement: |
      The HSP82/HSC82 family is essential: single deletion is viable but double disruption is
      lethal, and at least one cytosolic Hsp90 isoform is required for viability.
    supporting_text: |-
      Classic yeast genetics and biochemistry established that the HSP82/HSC82 family is **essential** (double disruption lethal), and that Hsp90 supports key signaling regulators.
    reference_section_type: RESULTS
  - statement: |
      Cytosolic Hsp90 (Hsp82/Hsc82) is broadly distributed during vegetative growth but
      accumulates in the nucleus in quiescent cells (glucose exhaustion) and in sporulating
      diploids, where nuclear accumulation defects correlate with sporulation/spore-wall defects.
    supporting_text: |-
      **Condition-dependent nuclear accumulation:** A key cell-biological finding is that Hsp90 (and the cochaperone Sba1/p23) **accumulates in the nucleus in quiescent cells (glucose exhaustion)** and in sporulating diploids; nuclear accumulation defects correlate with **sporulation/spore-wall defects**, and pharmacological inhibition (macbecin) similarly disrupts nuclear accumulation and spore development.
    reference_section_type: RESULTS
suggested_questions:
- question: Which client proteins (kinases, transcription factors, ribosome assembly factors) most strongly depend on HSP82 ATPase rate, and how does the rate-limiting step of the conformational cycle map to client maturation efficiency?
- question: How does the HSP82/HSC82 paralog ratio shift the chaperone interactome composition (co-chaperones, clients) under heat versus standard growth, and what fraction of clients are paralog-specific?
- question: What role does single-site phosphorylation (e.g., starvation-dependent) play in compartment-specific HSP82 localization (nucleus vs cytoplasm) and client engagement?
suggested_experiments:
- description: Deplete or inhibit HSP82 (e.g., temperature-sensitive alleles, radicicol) and use AP-MS to map condition-dependent client losses, comparing standard growth to heat shock and starvation conditions to dissect core vs. stress-specific clientele.
- description: Reconstitute the full Hsp82 conformational cycle in vitro with purified HSP82 dimers, ATP, and a panel of co-chaperones (Sti1, Aha1, Sba1, Cdc37, Cpr6/7, Cns1) plus a model client kinase, and use single-molecule FRET to measure ATP-dependent open/closed dwell times.
- description: Generate separation-of-function HSP82 alleles that selectively impair ATPase, dimerization, or co-chaperone binding (using systematic mutagenesis of the M-domain) and measure client-specific phenotypes (e.g., HAP1, telomerase, R2TP, proteasome) to dissect contributions to each downstream pathway.
tags:
- chaperone
- hsp90
- atp-dependent-foldase
- co-chaperone-network

HSP82

Gene Description

Existing Annotations Review

Core Functions

ATPase activity is fundamental to the Hsp90 chaperone cycle. Directly demonstrated by IDA (PMID:12235160) and IMP (PMID:27068472). Extensive mutagenesis data documents residues critical for ATPase activity.

References

Suggested Questions for Experts

Suggested Experiments

Tags

Deep Research

Falcon

Research Report: Functional Annotation of S. cerevisiae HSP82 (UniProt P02829)

0) Target identity verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 What Hsp82 does (primary function)

1.2 ATPase-coupled conformational cycle (mechanistic definition)

1.3 Co-chaperones (key definitions)

1.4 “Chaperone code” (PTM-based regulation)

2) Recent developments (prioritizing 2023–2024)

2.1 2024: Yeast-centered synthesis of mechanism and in vivo function

2.2 2023: Mutant dissection reveals cochaperones as “conformational pacemakers”

2.3 2024: Quantitative proteomics maps cycle-dependent client pools

3) Functional annotation narrative (processes, pathways, localization)

3.1 Biological processes and pathway roles

3.2 Cellular localization and where Hsp82 acts

4) Hsp82 vs Hsc82: specialization of two near-identical cytosolic isoforms

5) Applications and real-world implementations

5.1 Chemical-genetic screens and inhibitor studies in yeast

5.2 Industrial fermentation and yeast domestication (2024 Science)

6) Quantitative summary table (recent statistics)

7) Visual evidence (domain architecture and isoform comparison)

8) Practical functional-annotation statements (evidence-backed)

9) Notes on evidence limitations

Artifacts

Citations

📄 View Raw YAML