Hsp83

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Hsp83/HSP90 is a well-established molecular chaperone whose primary biological role is protein folding. The IBA annotation is supported by strong phylogenetic evidence across multiple orthologs (PMID:10716925, UniProt function annotation). UniProt states Hsp83 is a "Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins." Reason: Protein folding is the core biological process of HSP90 family chaperones. IBA is well-supported by orthologs and consistent with all functional literature on Hsp83. Supporting Evidence: PMID:10716925 a member of the highly conserved Hsp90 family including chaperones known to maintain the activity of many proteins file:DROME/Hsp83/Hsp83-deep-research-falcon.md Hsp83 is best understood as the cytosolic Hsp90 ATP-dependent chaperone that promotes late-stage folding/maturation, stabilization, and activation of diverse client proteins, especially those central to signaling and development
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: Hsp83/HSP90 has intrinsic ATPase activity that is essential for its chaperone cycle. The UniProt record notes it "Undergoes a functional cycle that is linked to its ATPase activity." The IBA annotation is supported by phylogenetic inference from multiple HSP90 orthologs with experimentally characterized ATPase activity. Reason: ATP hydrolysis is a core enzymatic activity of the HSP90 family. The HATPase_c domain is well characterized structurally and the ATPase cycle drives the chaperone conformational changes. Consistent with IBA evidence across the HSP90 family. Supporting Evidence: PMID:29775584 the Hsp90 system (Hop, Hsp90, and p23) together render Ago2 into an open, active form file:DROME/Hsp83/Hsp83-deep-research-falcon.md Mechanistically, Hsp90 proteins are dimeric, undergoing an ATP-driven conformational cycle involving ATP binding/hydrolysis and large structural rearrangements that enable remodeling/maturation of clients
GO:0032991 protein-containing complex	IBA GO_REF:0000033	ACCEPT	Summary: HSP90 family members function as homodimers and form multi-protein complexes with co-chaperones (Hop, p23, Cdc37, Aha1) and client proteins. UniProt states Hsp83 is a "Homodimer" and describes multiple complexes including with Hop/piwi, sicily/ND-42, Dpit47/Hsp70aa, and Nup358. The IBA annotation to the generic protein-containing complex is correct but very general. Reason: HSP90 is known to form multiple protein complexes. While the term is generic, IBA annotations at this level are acceptable as they reflect the phylogenetic inference. More specific complex annotations (GO:0101031, GO:0034663) are captured elsewhere.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation to plasma membrane is supported by phylogenetic inference from multiple HSP90 orthologs. Hsp83 was also detected at the plasma membrane by HDA (PMID:19317464). Hsp90 has an amphipathic helix that allows membrane interaction (PMID:30193096), which could explain plasma membrane localization. Reason: Plasma membrane localization is consistent with both the IBA evidence from orthologs and the independent HDA evidence from proteomics (PMID:19317464). The amphipathic helix-mediated membrane interaction described in PMID:30193096 provides a mechanistic basis. Supporting Evidence: PMID:30193096 Hsp90 also has the ability to directly interact with and deform membranes via an evolutionarily conserved amphipathic helix
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: ATP binding is a fundamental property of HSP90 family members, mediated by the HATPase_c domain. UniProt lists multiple ATP binding residues (positions 39, 81, 100, 126, 385) and the keyword "ATP-binding." IBA annotation is well supported. Reason: ATP binding is intrinsic to the HSP90 ATPase domain. Structurally characterized across the family.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosolic localization of HSP90 family members is well established. IBA annotation from multiple orthologs. Consistent with UniProt subcellular location annotation to "Cytoplasm" and multiple IDA/HDA annotations to cytoplasm in Drosophila. Reason: Cytosol is the primary localization for cytoplasmic HSP90 family members. IBA is well supported.
GO:0050821 protein stabilization	IBA GO_REF:0000033	ACCEPT	Summary: HSP90 chaperones stabilize client proteins, preventing their degradation. UniProt states Hsp83 "promotes the maturation, structural maintenance and proper regulation of specific target proteins." IBA from multiple orthologs. Loss of Hsp90 function leads to decreased levels of client proteins such as ND42 and NDUFS3 (PMID:23509070), directly demonstrating protein stabilization. Reason: Protein stabilization is a core function of HSP90 -- client proteins are destabilized and degraded when HSP90 is inhibited. Well supported by phylogenetic evidence and direct experimental data in Drosophila. Supporting Evidence: PMID:23509070 Both NDUFS3 and ND42 are severely down-regulated in sicily mutants, whereas other mitochondrial proteins, including Porin (Graham et al., 2010) and cytochrome c, are unaltered or slightly increased file:DROME/Hsp83/Hsp83-deep-research-falcon.md Hsp83 is best understood as the cytosolic Hsp90 ATP-dependent chaperone that promotes late-stage folding/maturation, stabilization, and activation of diverse client proteins, especially those central to signaling and development
GO:0034605 cellular response to heat	IBA GO_REF:0000033	ACCEPT	Summary: Hsp83 is a heat shock protein that is upregulated in response to heat stress. IBA from multiple orthologs. Consistent with IEP evidence from PMID:16595740 showing Hsp83 protein levels increase after heat shock. Name itself (Heat shock protein 83) reflects this function. Reason: Cellular response to heat is a defining characteristic of heat shock proteins. IBA supported by expression and functional data in Drosophila. Supporting Evidence: PMID:16595740 increases in the levels of Hsp83 and DnaJ-1 proteins but not in the inducible form of Hsp70 were detected by Western blot analysis
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 "unfolded protein binding" is now formally obsolete. HSP90 does not simply bind unfolded proteins like holdase chaperones; rather, it acts as an ATP-dependent foldase that binds near-native client proteins and assists their maturation through conformational change driven by ATP hydrolysis. The correct MF term is GO:0140662 "ATP-dependent protein folding chaperone." Reason: GO:0051082 is now formally obsolete and does not accurately describe the HSP90 mechanism. HSP90 does not primarily bind unfolded proteins; it binds near-native, partially folded client proteins and uses ATP hydrolysis to drive their maturation. The replacement term GO:0140662 "ATP-dependent protein folding chaperone" precisely captures the molecular function. Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:29775584 the Hsp90 system is required to extend the dwell time of Ago2 in the open state, which must be transiently primed by the Hsp70 system
GO:0048471 perinuclear region of cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation to perinuclear region of cytoplasm is supported by phylogenetic inference from multiple orthologs. Also supported by direct experimental evidence in Drosophila (IDA, PMID:22902557) where Hsp83 was observed in perinuclear region via the piRNA pathway work with Shutdown (Shu). Reason: Consistent with IBA evidence and directly confirmed by IDA in Drosophila (PMID:22902557).
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProtKB keyword mapping (KW-0547 "Nucleotide-binding"). Hsp83 is indeed an ATP-binding protein with a well-characterized nucleotide binding pocket. This is a broader parent term of ATP binding (GO:0005524) which is already annotated with IBA evidence. Reason: Correct but redundant with the more specific ATP binding annotation. IEA annotations at broader levels than IBA are acceptable.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP binding from combined automated methods (InterPro:IPR001404, InterPro:IPR019805, UniProtKB-KW:KW-0067). Correct and consistent with IBA annotation for the same term. Reason: Redundant with IBA annotation for the same GO term. Both are correct. Hsp83 has a well-characterized HATPase domain.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location vocabulary mapping. UniProt annotates Hsp83 subcellular location as "Cytoplasm." Consistent with multiple IDA and HDA annotations for cytoplasm. Reason: Correct. Cytoplasmic localization is well established by multiple independent lines of evidence.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain mapping (IPR001404, IPR019805). Protein folding is the core biological process of HSP90 family. Consistent with IBA and other evidence. Reason: Correct. Redundant with IBA annotation. InterPro correctly maps the HSP90 domain to the protein folding process.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain mapping (IPR001404). ATP hydrolysis is intrinsic to the HATPase domain of HSP90. Consistent with IBA. Reason: Correct. Redundant with IBA annotation. InterPro correctly maps the HSP90 HATPase domain to ATP hydrolysis activity.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation from InterPro domain mapping. GO:0051082 is now formally obsolete. HSP90 does not function as a holdase chaperone that binds unfolded proteins; it is an ATP-dependent foldase that acts on near-native client proteins. Reason: Same issue as the IBA annotation for this term. GO:0051082 is now formally obsolete and does not accurately represent the HSP90 mechanism. Should be replaced with GO:0140662 "ATP-dependent protein folding chaperone." Proposed replacements: ATP-dependent protein folding chaperone
GO:0101031 protein folding chaperone complex	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning model (ARBA:ARBA00026483). HSP90 forms multiple chaperone complexes. Consistent with IDA evidence from PMID:33176138 for the same term. Reason: Correct. HSP90 is a core component of protein folding chaperone complexes. Consistent with direct experimental evidence in Drosophila.
GO:0140662 ATP-dependent protein folding chaperone	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain mapping (IPR001404). GO:0140662 "ATP-dependent protein folding chaperone" is the correct molecular function term for HSP90, accurately capturing its ATP-dependent chaperone mechanism. This is the term that should replace GO:0051082 across all annotations. Reason: This is the most accurate MF term for HSP90 function. HSP90 binds client proteins and assists their folding/maturation through ATP hydrolysis-driven conformational changes. Supporting Evidence: PMID:29775584 the Hsp90 system is required to extend the dwell time of Ago2 in the open state
GO:0005515 protein binding	IPI PMID:22579285 Hsp90 globally targets paused RNA polymerase to regulate gen...	MARK AS OVER ANNOTATED	Summary: IPI annotation from IntAct based on physical interaction with Nelf-E (P92204). PMID:22579285 showed Hsp90 localizes to promoters and stabilizes the NELF complex to maintain RNA polymerase II pausing. While the interaction is real, "protein binding" is uninformative. Reason: The interaction with Nelf-E is likely reflecting Hsp83's chaperone activity on NELF complex stabilization. "Protein binding" is too generic and uninformative. The chaperone function is better captured by GO:0140662, and the biological outcome (gene expression regulation) is a downstream effect of chaperone activity. Supporting Evidence: PMID:22579285 Hsp90 maintains and optimizes RNA polymerase II pausing via stabilization of the negative elongation factor complex (NELF)
GO:0034663 endoplasmic reticulum chaperone complex	IPI PMID:22099462 XPORT-dependent transport of TRP and rhodopsin.	MARK AS OVER ANNOTATED	Summary: IPI annotation based on physical interaction evidence (PMID:22099462), with interactors FB:FBgn0038749 and FB:FBgn0289994. PMID:22099462 identifies XPORT as a chaperone for TRP and rhodopsin that interacts with Hsp90 in the ER/secretory pathway. Hsp83 is primarily a cytoplasmic chaperone, and ER localization would be atypical for the cytoplasmic HSP90 (as opposed to ER-resident GRP94/Hsp90B1). Reason: PMID:22099462 shows XPORT (a resident ER/secretory-pathway protein) interacts with Hsp90, but the IPI-based CC annotation to an ER chaperone complex over-interprets this transient interaction. Falcon deep research confirms Hsp83 is the sole CYTOSOLIC Hsp90-family chaperone in D. melanogaster and is primarily cytosolic; stable residence in an ER chaperone complex would be atypical for the cytoplasmic HSP90 (the ER-resident Hsp90 paralog is GRP94/ Hsp90B1, encoded separately by Gp93 in flies). The most parsimonious interpretation is a transient cytosolic-side interaction of Hsp83 with XPORT during client (TRP/Rh1) processing rather than bona fide membership of an ER chaperone complex. The chaperone activity itself is better captured by GO:0140662 and GO:0101031. Supporting Evidence: PMID:22099462 XPORT is a resident ER and secretory pathway protein that interacts with TRP and Rh1, as well as with Hsp27 and Hsp90 file:DROME/Hsp83/Hsp83-deep-research-falcon.md Hsp83 is the sole cytosolic Hsp90-family chaperone in D. melanogaster and functions as an ATP-dependent molecular chaperone that promotes late-stage folding, maturation, stabilization, and activation of signaling clients.
GO:0005739 mitochondrion	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from human HSP90AA1 (P07900). A minor pool of HSP90 has been reported in mitochondria in mammalian cells. Hsp83 interacts with Sicily for chaperoning ND42 before mitochondrial import (PMID:23509070), but this occurs in the cytoplasm. Mitochondrial localization of the fly protein itself is not directly demonstrated. Reason: Mitochondrial localization is plausible based on mammalian ortholog data but not directly demonstrated in Drosophila. The cytoplasmic chaperoning of mitochondrial proteins (PMID:23509070) does not require Hsp83 itself to localize to mitochondria. Supporting Evidence: PMID:23509070 Sicily preprotein interacts with cytosolic Hsp90 to chaperone the CI subunit, ND42, before mitochondrial import
GO:0097753 membrane bending	IDA PMID:30193096 Hsp90 Mediates Membrane Deformation and Exosome Release.	KEEP AS NON CORE	Summary: IDA annotation based on direct demonstration in PMID:30193096 that Hsp90 can directly interact with and deform membranes via an evolutionarily conserved amphipathic helix. This is a non-chaperone function structurally separated from the protein folding activity. Reason: Membrane bending is a genuine, experimentally validated function of Hsp90 mediated by its amphipathic helix. However, it is a non-canonical function distinct from the core chaperone activity and therefore non-core. The paper explicitly states they "structurally separated the Hsp90 membrane-deforming function from its well-characterized chaperone activity." Supporting Evidence: PMID:30193096 Hsp90 also has the ability to directly interact with and deform membranes via an evolutionarily conserved amphipathic helix PMID:30193096 we structurally separated the Hsp90 membrane-deforming function from its well-characterized chaperone activity
GO:0098866 multivesicular body fusion to apical plasma membrane	IMP PMID:30193096 Hsp90 Mediates Membrane Deformation and Exosome Release.	KEEP AS NON CORE	Summary: IMP annotation from PMID:30193096. The amphipathic helix of Hsp90 promotes the fusion of multivesicular bodies (MVBs) with the plasma membrane, enabling exosome release. Mutations and drugs that stabilize the open Hsp90 dimer expose the helix and allow MVB fusion. Reason: This is a genuine but non-core function mediated by the non-chaperone membrane-deforming activity of Hsp90. Not a typical chaperone function. Supporting Evidence: PMID:30193096 this amphipathic helix allows exosome release by promoting the fusion of multivesicular bodies (MVBs) with the plasma membrane
GO:0070922 RISC complex assembly	IGI PMID:29775584 Conformational Activation of Argonaute by Distinct yet Coord...	ACCEPT	Summary: IGI annotation from PMID:29775584 with genetic interactors FB:FBgn0037728 and FB:FBgn0266599. The paper demonstrates that Hsp70/Hsp90 chaperone machinery is required for loading small RNAs into Argonaute, a key step in RISC assembly. The Hsp90 system captures and stabilizes the open, active form of Ago2. Reason: RISC complex assembly is a well-characterized function of the Hsp90 chaperone system. Hsp90 is required for conformational activation of Argonaute to enable small RNA loading. This is a specific manifestation of its core chaperone function on a defined client protein complex. Supporting Evidence: PMID:29775584 Loading of small RNAs into Argonaute, the core protein in RNA silencing, requires the Hsp70/Hsp90 chaperone machinery PMID:29775584 the Hsp90 system is required to extend the dwell time of Ago2 in the open state
GO:0070922 RISC complex assembly	IPI PMID:33176138 Modulation of Ago2 Loading by Cyclophilin 40 Endows a Unique...	ACCEPT	Summary: IPI annotation from PMID:33176138 with interactors FB:FBgn0036020, FB:FBgn0087035, and FB:FBgn0262739. PMID:33176138 identifies Cyclophilin 40 as a testis-specialized Hsp90 co-chaperone that modulates Ago2-RISC formation. Cyp40 interacts with Ago2 through Hsp90 and promotes the build-up of Ago2-bound miRNAs. Reason: Consistent with the IGI evidence from PMID:29775584 and with the known role of HSP90 in Argonaute maturation and RISC assembly. Additional IPI evidence strengthens the annotation. Supporting Evidence: PMID:33176138 Cyp40 interacts with duplex-incorporating Ago2 through Hsp90 in vitro and selectively promotes the build-up of Ago2-bound miRNAs
GO:0005515 protein binding	IPI PMID:31907206 Drosophila Morgana is an Hsp90-interacting protein with a di...	MARK AS OVER ANNOTATED	Summary: IPI annotation from UniProt based on interaction with Morgana/CHORD (Q9VCC0). PMID:31907206 showed that Morgana co-purifies with the Hsp90-R2TP-TTT supercomplex. This is a typical co-chaperone interaction. Reason: "Protein binding" is uninformative. The interaction with Morgana reflects Hsp83's role as part of the Hsp90-R2TP-TTT chaperone supercomplex. This is better captured by the chaperone complex annotations (GO:0101031) and the ATP-dependent protein folding chaperone MF term (GO:0140662). Supporting Evidence: PMID:31907206 Mora localises to mitotic spindles and co-purifies with the Hsp90-R2TP-TTT supercomplex and with additional well-known Hsp90 co-chaperones
GO:0016887 ATP hydrolysis activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from human HSP90AA1 (P07900). ATP hydrolysis is well established for HSP90 family members. Consistent with IBA evidence for the same term. Reason: Correct. Redundant with IBA. ATP hydrolysis is a core function of the HSP90 family.
GO:0101031 protein folding chaperone complex	IDA PMID:33176138 Modulation of Ago2 Loading by Cyclophilin 40 Endows a Unique...	ACCEPT	Summary: IDA annotation from PMID:33176138 directly demonstrating Hsp83 as part of a protein folding chaperone complex. PMID:33176138 shows Hsp90 machinery acts as chaperone complex for Ago2 loading during RISC assembly. HSP90 forms complexes with co-chaperones (Hop, p23, Cdc37, Cyp40, etc.) to constitute chaperone machinery. Reason: HSP90 is a core component of chaperone complexes. IDA evidence directly confirms this in Drosophila. Consistent with UniProt subunit annotations describing multiple Hsp83-containing complexes. Supporting Evidence: PMID:33176138 In gene silencing, Hsp90 chaperone machinery assists Argonaute (Ago) binding and unwinding of silencing small RNA (sRNA) duplexes
GO:0005515 protein binding	IPI PMID:23509070 The C8ORF38 homologue Sicily is a cytosolic chaperone for a ...	MARK AS OVER ANNOTATED	Summary: IPI annotation from UniProt based on interaction with Sicily (P91929) and ND-42/NDUFA10 (Q9VYS5). PMID:23509070 showed Sicily is a cytosolic chaperone for a mitochondrial Complex I subunit, and Hsp83 forms a complex with Sicily and ND42. Hsp90 binds to Sicily directly and coimmunoprecipitates ND42 only when Sicily is coexpressed. Reason: "Protein binding" is uninformative. The interaction with Sicily reflects Hsp83's chaperone function in chaperoning ND42 before mitochondrial import. Better captured by the ATP-dependent protein folding chaperone MF term (GO:0140662) and the protein stabilization BP term (GO:0050821). Supporting Evidence: PMID:23509070 Hsp90 binds to Sicily in an in vitro co-IP assay
GO:0002052 positive regulation of neuroblast proliferation	IMP PMID:30245208 Hsp83/Hsp90 Physically Associates with Insulin Receptor to P...	KEEP AS NON CORE	Summary: IMP annotation from PMID:30245208. Hsp83 is both necessary and sufficient for neural stem cell reactivation by promoting the activation of InR pathway in larval brains. This is a downstream pleiotropic effect of Hsp83 chaperone function on signaling clients. Reason: This is a downstream developmental phenotype of Hsp83 function, likely mediated through its role in insulin receptor signaling (same paper provides insulin receptor binding annotation). Non-core pleiotropic effect. Supporting Evidence: PMID:30245208 Hsp83 is both necessary and sufficient for NSC reactivation by promoting the activation of InR pathway in larval brains in the presence of dietary amino acids
GO:0005158 insulin receptor binding	IDA PMID:30245208 Hsp83/Hsp90 Physically Associates with Insulin Receptor to P...	KEEP AS NON CORE	Summary: IDA annotation from PMID:30245208 demonstrating direct binding of Hsp83 to the insulin receptor. Both Hsp83 and its co-chaperone Cdc37 physically associate with InR. HSP90 is known to chaperone receptor tyrosine kinases in other systems. This likely reflects HSP90's general role in chaperoning kinase clients. Reason: Insulin receptor binding is consistent with HSP90's well-known role as a kinase chaperone, but it represents a specific client interaction rather than a core molecular function. The core function is the ATP-dependent protein folding chaperone activity. Supporting Evidence: PMID:30245208 Both Hsp83 and its co-chaperone Cdc37 physically associate with InR
GO:0046628 positive regulation of insulin receptor signaling pathway	IGI PMID:30245208 Hsp83/Hsp90 Physically Associates with Insulin Receptor to P...	KEEP AS NON CORE	Summary: IGI annotation from PMID:30245208 with genetic interactor FB:FBgn0283499. Hsp83 positively regulates insulin receptor signaling, consistent with its role in chaperoning the insulin receptor. Reason: Downstream pleiotropic effect of Hsp83 chaperone function on insulin signaling. Non-core but experimentally supported. Supporting Evidence: PMID:30245208 Hsp83 is both necessary and sufficient for NSC reactivation by promoting the activation of InR pathway in larval brains in the presence of dietary amino acids
GO:0005737 cytoplasm	HDA PMID:26896675 A genome-wide resource for the analysis of protein localisat...	ACCEPT	Summary: HDA annotation from a genome-wide protein localization study (PMID:26896675) using GFP-tagged fosmid transgenes in Drosophila. Cytoplasmic localization is consistent with all other evidence. Reason: Cytoplasm is the primary localization for Hsp83. Confirmed by multiple independent methods. Supporting Evidence: PMID:26896675 A genome-wide resource for the analysis of protein localisation in Drosophila
GO:0030911 TPR domain binding	IPI PMID:27979731 Nucleoporin Nup358 facilitates nuclear import of Methoprene-...	ACCEPT	Summary: IPI annotation from PMID:27979731 based on interaction of Hsp83 with the TPR domain of Nup358. The C-terminal MEEVD motif of HSP90 is a well-characterized TPR repeat-binding motif (UniProt: "The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins"). The interaction with Nup358 TPR domain facilitates nuclear import of Met, the juvenile hormone receptor. Reason: TPR domain binding is a core molecular function of HSP90 family members, mediated by the conserved C-terminal MEEVD motif. This is how HSP90 interacts with many co-chaperones (Hop, CHIP, Tom70, etc.) and other TPR-containing proteins. Supporting Evidence: PMID:27979731 a tetratricopeptide repeat (TPR) domain at the N-terminal end of Nup358 interacts with Hsp83 and is indispensable for Met nuclear localization file:DROME/Hsp83/Hsp83-deep-research-falcon.md Key named regulators include Cdc37 (kinase client recruitment), p23, and Aha1, as well as TPR-domain proteins such as Hop that bind the conserved MEEVD C-terminal motif typical of cytosolic Hsp90s
GO:0006457 protein folding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from yeast HSP82 (P15108). Protein folding is well established for HSP90 family. Consistent with IBA and IEA evidence. Reason: Correct. Redundant with IBA and IEA. Protein folding is the core biological process.
GO:0034605 cellular response to heat	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation transferred from yeast HSP82 (P15108). Cellular response to heat is well established for heat shock proteins. Consistent with IBA evidence. Reason: Correct. Redundant with IBA. Heat shock response is a defining feature of HSP90 family.
GO:0043248 proteasome assembly	IDA PMID:15946124 Zn2+-induced reversible dissociation of subunit Rpn10/p54 of...	KEEP AS NON CORE	Summary: IDA annotation from PMID:15946124. Hsp82 (Hsp83) was identified by mass spectrometry as the main Rpn10/p54-interacting protein after Zn2+-induced proteasome disassembly, suggesting a role in reassembly of the 26S proteasome. Reason: The evidence shows Hsp83 interacts with Rpn10 after proteasome disassembly, suggesting a role in reassembly. This is consistent with HSP90's general chaperone function applied to proteasome components, but represents a specific client relationship rather than a core function. Supporting Evidence: PMID:15946124 Hsp82 (heat-shock protein 82) has been identified by MS as the main Rpn10/p54-interacting protein, suggesting its role in the reassembly of the 26 S proteasome after Zn2+ removal
GO:0005737 cytoplasm	HDA PMID:24292889 Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and...	ACCEPT	Summary: HDA annotation from PMID:24292889 (Ube3a proteasomal shuttle Rpn10 study). Cytoplasmic localization detected as part of a high-throughput study. Consistent with other evidence. Reason: Cytoplasm localization is well established. Additional HDA evidence. Supporting Evidence: PMID:24292889 Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells
GO:0005886 plasma membrane	HDA PMID:19317464 Mapping organelle proteins and protein complexes in Drosophi...	ACCEPT	Summary: HDA annotation from PMID:19317464 (LOPIT subcellular proteomics study in Drosophila embryos). Plasma membrane localization detected in this systematic study. Consistent with IBA annotation and the amphipathic helix-mediated membrane interaction (PMID:30193096). Reason: Plasma membrane localization supported by independent proteomics evidence and consistent with IBA and the membrane-deforming function. Supporting Evidence: PMID:19317464 we apply LOPIT, a mass-spectrometry based technique that simultaneously maps proteins to specific subcellular compartments, to Drosophila embryos
GO:0051082 unfolded protein binding	IDA PMID:18344983 NAD synthase NMNAT acts as a chaperone to protect against ne...	MODIFY	Summary: IDA annotation from PMID:18344983. This paper is primarily about NMNAT as a chaperone, not about Hsp83 directly. The paper shows that NMNAT "displays chaperone function both in biochemical assays and cultured cells" and compares it to Hsp70. Hsp83 is mentioned as a control or comparison. Regardless, GO:0051082 is now formally obsolete and the term does not correctly describe HSP90 function. HSP90 is an ATP-dependent foldase, not a holdase. Reason: GO:0051082 is now formally obsolete. The evidence in PMID:18344983 is primarily about NMNAT chaperone function, with Hsp83 as a comparison. The correct term for Hsp83 molecular function is GO:0140662 "ATP-dependent protein folding chaperone." Proposed replacements: ATP-dependent protein folding chaperone Supporting Evidence: PMID:18344983 NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones
GO:0008285 negative regulation of cell population proliferation	IMP PMID:24086162 The molecular chaperone Hsp90 is required for cell cycle exi...	KEEP AS NON CORE	Summary: IMP annotation from PMID:24086162. Hsp83 mutation results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues, demonstrating that Hsp83 is required for proper cell cycle exit. The paper proposes Cdh1/Fzr (APC/C activating subunit) is a client of Hsp83. Thus Hsp83 indirectly promotes cell cycle exit by chaperoning APC/C components. Reason: This is a downstream phenotypic consequence of Hsp83 chaperone function on cell cycle regulators (APC/C components). The paper proposes "Cdh1/Fzr is a client protein of Hsp83." This is a pleiotropic effect of the core chaperone function, not a core function itself. Supporting Evidence: PMID:24086162 Mutation of Hsp83, the Drosophila homolog of mammalian Hsp90, results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues at a time when neighboring wild-type cells are postmitotic PMID:24086162 we propose that Cdh1/Fzr is a client protein of Hsp83 file:DROME/Hsp83/Hsp83-deep-research-falcon.md In Hsp83(6-55) mutant clones, E2F-dependent transcription increases and cells show ectopic S phase and mitosis after neighboring cells have exited the cell cycle
GO:0048471 perinuclear region of cytoplasm	IDA PMID:22902557 The cochaperone shutdown defines a group of biogenesis facto...	ACCEPT	Summary: IDA annotation from PMID:22902557. This paper studies the cochaperone Shutdown and piRNA biogenesis. Using a genomic GFP-tagged Hsp83 construct, the authors show that Hsp83 is enriched in a peri-nuclear rim in wild-type nurse cells, potentially reflecting nuage accumulation. Hsp83 colocalizes with unloaded AGO3 in cytoplasmic foci when piRNA biogenesis is disrupted. Reason: Perinuclear region localization is directly demonstrated by IDA using GFP-tagged Hsp83 and is consistent with IBA evidence and the known role of Hsp83 in piRNA biogenesis in germline nuage. Supporting Evidence: PMID:22902557 Hsp83 was enriched in a peri-nuclear rim, potentially reflecting nuage accumulation
GO:0005705 polytene chromosome interband	IDA PMID:19144915 Trithorax requires Hsp90 for maintenance of active chromatin...	ACCEPT	Summary: IDA annotation from PMID:19144915. This paper shows a direct molecular interaction between Hsp90 and Trithorax, and that Hsp90 cooperates with Trx at chromatin for maintaining the active expression state of targets like Hox genes. Polytene chromosome interband localization is consistent with the chromatin-binding function of Hsp90. Reason: PMID:19144915 demonstrates Hsp90 interacts with Trithorax at chromatin to maintain active gene expression. Polytene chromosome interband localization is consistent with this chromatin-associated function and with the finding from PMID:22579285 that Hsp90 localizes to promoters. Supporting Evidence: PMID:19144915 Hsp90 cooperates with Trx at chromatin for maintaining the active expression state of targets like the Hox genes
GO:0005737 cytoplasm	IDA PMID:19144915 Trithorax requires Hsp90 for maintenance of active chromatin...	ACCEPT	Summary: IDA annotation from PMID:19144915. Cytoplasmic localization is consistent with all other evidence. Reason: Cytoplasm localization is independently confirmed by many other studies. This annotation is redundant but correct. Supporting Evidence: PMID:19144915 Molecular chaperone heat-shock protein 90 kDa (Hsp90) is known to facilitate the conformational maturation of a diverse range of proteins involved in different signal transduction pathways during development
GO:0009631 cold acclimation	IEP PMID:16313561 Cold hardening and transcriptional change in Drosophila mela...	KEEP AS NON CORE	Summary: IEP annotation from PMID:16313561. Microarray analysis showed Hsp83 transcript was differentially expressed after cold hardening treatment (0 C for 2 h followed by recovery). The evidence is expression-based only (IEP), and does not demonstrate a direct functional role. Reason: Based solely on expression evidence (IEP). Transcript upregulation during cold hardening does not prove a direct role in cold acclimation. However, Hsp83 may contribute to protein homeostasis under cold stress. Keeping as non-core due to indirect evidence. Supporting Evidence: PMID:16313561 stress proteins, including Hsp23, Hsp26, Hsp83 and Frost as well as membrane-associated proteins may contribute to the cold hardening response
GO:0009408 response to heat	IEP PMID:16595740 Thermoprotection of synaptic transmission in a Drosophila he...	ACCEPT	Summary: IEP annotation from PMID:16595740. Hsp83 protein levels were shown to increase after heat shock by Western blot analysis, even in a heat shock factor mutant (hsf4). As a constitutively expressed heat shock protein, Hsp83 upregulation during heat stress provides thermoprotection at synapses. Reason: While IEP is weaker evidence, the response to heat is fundamental to heat shock proteins. The name "Heat shock protein 83" itself reflects this. The more specific term "cellular response to heat" (GO:0034605) is also annotated with IBA and ISS evidence. Falcon deep research adds an important nuance: Hsp83 is largely a constitutive proteostasis factor and is NOT transcriptionally induced in every proteotoxic stress state (e.g., in a 2023 larval fat body study Hsp83 and Gp93 did not change despite induction of Hsp70/Hsp40-class genes). The response-to-heat annotation remains valid (protein levels do rise after heat shock per PMID:16595740), but it reflects a partially constitutive, context- dependent thermoprotective role rather than a universally inducible response. Supporting Evidence: PMID:16595740 the compensatory upregulation of constitutively expressed Hsps, in the absence of the synthesis of the major inducible Hsp, Hsp70, could still provide substantial thermoprotection file:DROME/Hsp83/Hsp83-deep-research-falcon.md A 2023 Nature Communications study in Drosophila larval fat body found that Nacα reduction activates a heat shock response, with upregulation of Hsp70/Hsp40 class genes and oxidative stress markers, but Hsp83 (and another Hsp90-family gene Gp93) did not change in that context (qRT-PCR, n=4 batches)
GO:0005737 cytoplasm	IDA PMID:19101615 The molecular chaperone Hsp90 is a component of the cap-bind...	ACCEPT	Summary: IDA annotation from PMID:19101615. Hsp90 and Cup co-localize in the cytoplasm of developing germ-line cells within the germarium. Reason: Cytoplasmic localization directly demonstrated during oogenesis. Consistent with all other cytoplasm annotations. Supporting Evidence: PMID:19101615 Hsp90 and Cup co-localize in the cytoplasm of the developing germ-line cells within the germarium
GO:0048477 oogenesis	IGI PMID:19101615 The molecular chaperone Hsp90 is a component of the cap-bind...	KEEP AS NON CORE	Summary: IGI annotation from PMID:19101615 with genetic interactor Cup (FB:FBgn0000392). Lowering Hsp90 activity enhances oogenesis alterations linked to diverse cup mutant alleles, demonstrating a genetic interaction in oogenesis. Hsp90 is a component of the cap-binding complex and interacts with the translational repressor Cup during oogenesis. Reason: Oogenesis involvement is a pleiotropic consequence of Hsp83 chaperone function during development. The paper shows Hsp90 participates in translational regulation during oogenesis via the cap-binding complex. This is a downstream developmental role, not a core function. Supporting Evidence: PMID:19101615 lowering Hsp90 activity enhances the oogenesis alterations linked to diverse cup mutant alleles file:DROME/Hsp83/Hsp83-deep-research-falcon.md Hsp83 also contributes to female fertility, oogenesis, and maternal RNA regulation. It interacts with the translational regulator Cup during oogenesis, localizes maternal transcripts, and affects nanos mRNA localization, linking Hsp83 to anterior–posterior patterning in embryos.
GO:0019094 pole plasm mRNA localization	IMP PMID:17565952 The molecular chaperone Hsp90 is required for mRNA localizat...	KEEP AS NON CORE	Summary: IMP annotation from PMID:17565952. Genetic approaches show that Hsp83/Hsp90 is a localization factor for nanos and pgc mRNAs. When Hsp90 function is partially compromised, nanos and pgc mRNA localization is disrupted while other pole plasm components are unaffected. The mechanism appears to involve Hsp90 chaperoning LKB1 kinase (for pgc) and other partners (for nos). Reason: This is a specific developmental role of Hsp83 in mRNA localization during embryogenesis, likely mediated through its chaperone function on LKB1 kinase and other clients. Non-core pleiotropic effect. Supporting Evidence: PMID:17565952 the Hsp90 chaperone (encoded by Hsp83 in Drosophila) is a localization factor for two mRNAs, nanos and pgc PMID:17565952 levels of the LKB1 kinase are reduced in Hsp83 mutant egg chambers file:DROME/Hsp83/Hsp83-deep-research-falcon.md It interacts with the translational regulator Cup during oogenesis, localizes maternal transcripts, and affects nanos mRNA localization, linking Hsp83 to anterior–posterior patterning in embryos.
GO:0005813 centrosome	IDA PMID:10716925 Hsp90 is a core centrosomal component and is required at dif...	ACCEPT	Summary: IDA annotation from PMID:10716925. Mass spectrometry analysis of immunoisolated Drosophila centrosomes identified Hsp83. The association persists after microtubule depolymerizing drug treatment, indicating Hsp90 is a core centrosomal component. Reason: Directly demonstrated by mass spectrometry of purified centrosomes and confirmed to be a core centrosomal component that persists after microtubule depolymerization. Supporting Evidence: PMID:10716925 a fraction of the total Hsp90 pool is localized at the centrosome throughout the cell cycle PMID:10716925 This association between Hsp90 and the centrosome can be observed in purified centrosomes and after treatment with microtubule depolymerizing drugs, two criteria normally used to define core centrosomal components
GO:0006457 protein folding	TAS PMID:10716925 Hsp90 is a core centrosomal component and is required at dif...	ACCEPT	Summary: TAS annotation from PMID:10716925 which describes Hsp83 as "a member of the highly conserved Hsp90 family including chaperones known to maintain the activity of many proteins." The protein folding function is stated as established fact in the publication. Reason: Correct. Protein folding is the core function. Redundant with IBA, IEA, and ISS evidence. Supporting Evidence: PMID:10716925 a member of the highly conserved Hsp90 family including chaperones known to maintain the activity of many proteins
GO:0007098 centrosome cycle	IMP PMID:10716925 Hsp90 is a core centrosomal component and is required at dif...	KEEP AS NON CORE	Summary: IMP annotation from PMID:10716925. Disruption of Hsp90 function by mutations in Hsp83 or geldanamycin treatment results in abnormal centrosome separation and maturation, aberrant spindles, and impaired chromosome segregation. Reason: Centrosome cycle involvement is a downstream consequence of Hsp83 chaperone function on centrosome client proteins. Hsp90 is required for proper centrosome function, but this is a pleiotropic effect of its core chaperone activity. Supporting Evidence: PMID:10716925 Disruption of Hsp90 function by mutations in the Drosophila gene or treatment of mammalian cells with the Hsp90 inhibitor geldanamycin, results in abnormal centrosome separation and maturation, aberrant spindles and impaired chromosome segregation
GO:0045187 regulation of circadian sleep/wake cycle, sleep	IMP PMID:12015603 Stress response genes protect against lethal effects of slee...	KEEP AS NON CORE	Summary: IMP annotation from PMID:12015603. Flies carrying a mutation for Hsp83 showed exaggerated homeostatic sleep response and died after sleep deprivation, demonstrating that Hsp83 plays a protective role in sleep homeostasis. Reason: Sleep regulation is a pleiotropic downstream effect. Hsp83 mutants show exaggerated homeostatic response to sleep deprivation, but this likely reflects a general stress-protective role rather than a direct sleep-regulatory function. Supporting Evidence: PMID:12015603 flies carrying a mutation for the heat-shock protein Hsp83 (Hsp83(08445)) showed exaggerated homeostatic response and died after sleep deprivation
GO:0045187 regulation of circadian sleep/wake cycle, sleep	TAS PMID:12486704 Perchance to dream: solving the mystery of sleep through gen...	KEEP AS NON CORE	Summary: TAS annotation from PMID:12486704. This is a review article discussing sleep research in Drosophila and mouse, referencing the genetic approaches that identified Hsp83 mutants with sleep phenotypes. Reason: Consistent with the IMP annotation from PMID:12015603 for the same term. Sleep regulation is a non-core pleiotropic effect. Supporting Evidence: PMID:12486704 studies in both the mouse and fly have begun to reveal tantalizing suggestions about the underlying principles that regulate sleep homeostasis

Gene Description

Existing Annotations Review

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Deep Research

Falcon

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