Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21/HSP90 is a well-established molecular chaperone that promotes protein folding. This core function is supported by multiple lines of evidence including the role in myosin folding in muscle cells (PMID:21980476) and stabilization of client proteins such as DAF-11 guanylyl cyclase (PMID:10790386). Reason: Protein folding is the central molecular function of HSP90 proteins. The phylogenetic inference from IBA is fully consistent with experimental evidence showing DAF-21 participates in folding of myosin and other client proteins. Supporting Evidence: PMID:21980476 The dimeric molecular chaperone Hsp90 is an ATP-dependent cellular machine, which contributes to the activation and regulation of steroid receptors, protein kinases and several transcription factors PMID:10790386 daf-21 encodes the heat-shock protein 90 (Hsp90) file:worm/daf-21/daf-21-deep-research-falcon.md model: Edison Scientific Literature
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21 has been directly shown to possess ATPase activity. The E292K mutation (daf-21(p673)) reduces ATPase activity compared to wild-type (PMID:21980476), confirming ATP hydrolysis is integral to DAF-21 function. Reason: ATPase activity is a core enzymatic function of HSP90 proteins. Direct biochemical measurement confirms DAF-21 hydrolyzes ATP, and this activity is essential for chaperone function. Supporting Evidence: PMID:21980476 At 30°C, the ATPase activity of E292K-DAF-21 was found to be 0.1 min−1, while that of wt-DAF-21 was 0.6 min−1 (Figure 1B)
GO:0032991 protein-containing complex	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21 functions as a homodimer and forms multi-protein chaperone complexes with co-chaperones including CDC-37, STI-1, PPH-5, and UNC-45. The protein forms defined complexes with co-chaperones as demonstrated by analytical ultracentrifugation. Reason: HSP90 functioning in multi-protein complexes is a well-established core feature. Multiple publications document specific complexes containing DAF-21 with defined co-chaperones. Supporting Evidence: PMID:26593036 This increase in absorption reflects the binding of two molecules of PPH-5 to the CeHsp90 dimer
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: While IBA inference suggests plasma membrane localization based on orthologs, direct evidence for DAF-21 localization in C. elegans primarily shows cytoplasmic and perinuclear localization rather than plasma membrane association. Reason: The experimental evidence in C. elegans (PMID:12950278, PMID:21980476) shows cytoplasmic localization with enrichment in the perinuclear region. Membrane raft localization was detected by mass spectrometry (PMID:21070894) suggesting some membrane association, but this is not a primary localization site.
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: ATP binding is a fundamental property of HSP90 proteins required for the chaperone cycle. The crystal structure (PDB:4GQT) shows the N-terminal ATP binding domain of DAF-21, and functional studies confirm nucleotide-dependent conformational changes. Reason: ATP binding is essential for HSP90 chaperone function. Direct structural evidence from X-ray crystallography confirms the ATP binding domain, and functional studies demonstrate nucleotide-dependent behaviors. Supporting Evidence: PMID:21980476 The functionality of DAF-21 is confirmed by its ability to bind the cofactor Cep23, which specifically recognizes the hydrolysis competent state with closed N-terminal domains
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21 is localized to the cytoplasm based on immunolocalization studies. The protein shows predominantly cytoplasmic distribution with perinuclear enrichment. Reason: Cytoplasmic/cytosolic localization is consistent with the known biology of HSP90 as a cytosolic chaperone and directly supported by experimental evidence in C. elegans.
GO:0050821 protein stabilization	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21 stabilizes client proteins including DAF-11 guanylyl cyclase (required for chemosensory signaling) and WEE-1.3 kinase (required for cell cycle control in oocytes). This is a core chaperone function. Reason: Protein stabilization is a core HSP90 function. Multiple experimental studies in C. elegans demonstrate DAF-21 stabilizes specific client proteins. Supporting Evidence: PMID:10790386 daf-21 encodes the heat-shock protein 90 (Hsp90)
GO:0034605 cellular response to heat	IBA GO_REF:0000033	ACCEPT	Summary: DAF-21 plays a critical role in cellular response to heat stress. The protein is part of the HSF-1 pathway required for thermotolerance. Reason: Response to heat is a well-documented function of HSP90 proteins. Multiple C. elegans studies demonstrate DAF-21 involvement in heat stress response and thermotolerance. Supporting Evidence: PMID:29949773 We measured mRNA levels of a range of heat-inducible chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: As a molecular chaperone, DAF-21 binds to unfolded or misfolded client proteins to facilitate their proper folding. This is a core molecular function of HSP90. Reason: GO:0051082 is proposed for obsoletion. DAF-21/HSP90 is an ATP-dependent foldase chaperone. The appropriate replacement term is GO:0044183 (protein folding chaperone). Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21980476 The ATP-dependent molecular chaperone Hsp90 is required for the activation of a variety of client proteins involved in various cellular processes
GO:0048471 perinuclear region of cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Direct immunolocalization studies show DAF-21 protein is localized to the perinuclear region in somatic cells of C. elegans. Reason: Direct experimental evidence from PMID:12950278 confirms perinuclear localization in C. elegans, supporting the phylogenetic inference.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: Nucleotide binding, specifically ATP binding, is a core function of HSP90 proteins required for chaperone activity. This is a general parent term of ATP binding. Reason: Nucleotide (ATP) binding is essential for DAF-21 function. This IEA annotation is consistent with more specific experimental evidence for ATP binding and hydrolysis.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: ATP binding annotation based on InterPro domain analysis. Consistent with experimental evidence and IBA annotation. Reason: Duplicate of IBA annotation for ATP binding. Both computational and phylogenetic evidence support the well-established ATP binding function.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: Protein folding annotation from InterPro HSP90 domain. Consistent with IBA annotation and experimental evidence. Reason: Duplicate annotation for protein folding, a core HSP90 function supported by multiple evidence types.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: ATP hydrolysis activity annotation from InterPro HSP90 domain. Consistent with IBA annotation and direct biochemical evidence. Reason: Duplicate annotation for ATPase activity, supported by direct biochemical measurements (PMID:21980476, PMID:19559711).
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Perinuclear localization from UniProt subcellular location vocabulary mapping. Consistent with IBA and IDA evidence. Reason: Duplicate annotation for perinuclear localization supported by direct immunolocalization evidence (PMID:12950278).
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 is proposed for obsoletion. InterPro domain-based annotation consistent with the IBA annotation. Reason: GO:0051082 is proposed for obsoletion. DAF-21/HSP90 is an ATP-dependent foldase chaperone. The appropriate replacement term is GO:0044183 (protein folding chaperone). Consistent with MODIFY on IBA annotation. Proposed replacements: protein folding chaperone
GO:0101031 protein folding chaperone complex	IEA GO_REF:0000117	ACCEPT	Summary: DAF-21 functions in multiple chaperone complexes with co-chaperones as documented in ComplexPortal (CPX-3983, CPX-3984, CPX-4002, CPX-4003, CPX-4004). Reason: DAF-21 is part of defined chaperone complexes including Hsp90-CDC37, Hsp90-STI-1, and Hsp90-PPH-5 complexes. This is consistent with its function as a component of the cellular chaperone machinery. Supporting Evidence: PMID:26593036 This increase in absorption reflects the binding of two molecules of PPH-5 to the CeHsp90 dimer
GO:0140662 ATP-dependent protein folding chaperone	IEA GO_REF:0000002	ACCEPT	Summary: DAF-21 is an ATP-dependent protein folding chaperone. This molecular function term accurately captures the core activity of the protein. Reason: This term precisely describes DAF-21 function - it is an ATP-dependent chaperone that promotes protein folding. Well supported by experimental evidence. Supporting Evidence: PMID:21980476 The ATP-dependent molecular chaperone Hsp90 is required for the activation of a variety of client proteins involved in various cellular processes
GO:0005515 protein binding	IPI PMID:11809970 Role of the myosin assembly protein UNC-45 as a molecular ch...	MODIFY	Summary: This annotation captures DAF-21 interaction with UNC-45, an Hsp90 co-chaperone required for myosin folding. The interaction is functionally relevant for muscle cell maintenance. Reason: While the interaction with UNC-45 is valid, "protein binding" is too general and uninformative. The annotation would be better represented by a more specific term capturing the co-chaperone interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:11809970 Role of the myosin assembly protein UNC-45 as a molecular chaperone for myosin.
GO:0005515 protein binding	IPI PMID:14992718 Systematic interactome mapping and genetic perturbation anal...	MODIFY	Summary: Interaction with DAF-1 (TGF-beta type I receptor) identified in systematic interactome mapping of TGF-beta signaling network. Reason: While the protein interaction is valid, "protein binding" is too general. HSP90 chaperoning of receptor kinases is a known function. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:14992718 Systematic interactome mapping and genetic perturbation analysis of a C.
GO:0005515 protein binding	IPI PMID:19467242 C. elegans STI-1, the homolog of Sti1/Hop, is involved in ag...	MODIFY	Summary: Interaction with STI-1, the C. elegans Hop/Sti1 ortholog that functions as a co-chaperone linking Hsp70 and Hsp90 systems. Reason: The interaction with STI-1/Hop is a well-characterized co-chaperone interaction. A more specific term would be more informative. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:19467242 2009 May 23. C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and stress response.
GO:0005515 protein binding	IPI PMID:19559711 The non-canonical Hop protein from Caenorhabditis elegans ex...	MODIFY	Summary: Interaction with STI-1 confirmed biochemically. STI-1 inhibits DAF-21 ATPase activity upon binding. Reason: Duplicate annotation for STI-1 interaction. "Protein binding" is too vague for this well-characterized co-chaperone interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:19559711 2009 Jun 25. The non-canonical Hop protein from Caenorhabditis elegans exerts essential functions and forms binary complexes with either Hsc70 or Hsp90.
GO:0005515 protein binding	IPI PMID:23332754 The myosin chaperone UNC-45 is organized in tandem modules t...	MODIFY	Summary: Interaction with UNC-45 in the context of myofilament formation in C. elegans. Reason: Valid co-chaperone interaction. Recommend more specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:23332754 The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C.
GO:0005515 protein binding	IPI PMID:23746847 Regulation of organismal proteostasis by transcellular chape...	MODIFY	Summary: This study established transcellular chaperone signaling where HSP-90 in one tissue can induce proteostasis responses in other tissues. Reason: "Protein binding" is too general. This study demonstrates tissue-nonautonomous effects but the molecular interactions captured are not well-served by this term. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:23746847 Regulation of organismal proteostasis by transcellular chaperone signaling.
GO:0042802 identical protein binding	IPI PMID:14992718 Systematic interactome mapping and genetic perturbation anal...	ACCEPT	Summary: DAF-21 homodimerization is essential for HSP90 function. The protein exists as a homodimer with C-terminal dimerization domain. Reason: HSP90 homodimerization is a core structural feature required for chaperone function. This annotation correctly captures DAF-21 self-association. Supporting Evidence: PMID:26593036 This increase in absorption reflects the binding of two molecules of PPH-5 to the CeHsp90 dimer PMID:14992718 Systematic interactome mapping and genetic perturbation analysis of a C.
GO:0006457 protein folding	IDA PMID:21980476 Downregulation of the Hsp90 system causes defects in muscle ...	ACCEPT	Summary: Direct experimental evidence from RNAi knockdown and mutant analysis showing DAF-21 is required for proper myosin folding in muscle cells. Reduction of DAF-21 leads to myosin aggregation. Reason: Strong experimental evidence from direct assays showing DAF-21 is required for protein folding in vivo, particularly for myosin in muscle cells. Supporting Evidence: PMID:21980476 aggregates of the myosin MYO-3 are visible in muscle cells, if DAF-21 is depleted, implying a role of Hsp90 in the maintenance of muscle cell functionality
GO:0072542 protein phosphatase activator activity	IDA PMID:26593036 The activity of protein phosphatase 5 towards native clients...	ACCEPT	Summary: DAF-21 directly activates the protein phosphatase PPH-5 (PP5 ortholog). The interaction promotes PPH-5 phosphatase activity and is required for dephosphorylation of native clients. Reason: This is a well-characterized molecular function demonstrated through biochemical assays. DAF-21 activates PPH-5 phosphatase activity through direct interaction. Supporting Evidence: PMID:26593036 we observed an increase of the phosphatase activity in the presence of C. elegans Hsp90 (CeHsp90)
GO:0009408 response to heat	IGI PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for...	ACCEPT	Summary: DAF-21 is part of the HSF-1 pathway required for heat stress response and thermotolerance. The gene is required for immunity response to pathogens and heat stress survival. Reason: Heat stress response is a well-documented function of HSP90 proteins. The IGI evidence with HSF-1 demonstrates DAF-21 functions in the heat shock response pathway. Supporting Evidence: PMID:16916933 The HSF-1 defense response is independent of the p38 MAPK/PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins
GO:0050829 defense response to Gram-negative bacterium	IGI PMID:16916933 Heat-shock transcription factor (HSF)-1 pathway required for...	KEEP AS NON CORE	Summary: DAF-21 is required for C. elegans innate immunity against Gram-negative pathogens including Pseudomonas aeruginosa, as part of the HSF-1-mediated defense pathway. Reason: While HSP90 is part of the stress-induced immune response pathway, this represents a downstream consequence of chaperone function rather than a core molecular activity. Keep as non-core biological function. Supporting Evidence: PMID:16916933 HSF-1 is required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis
GO:0034605 cellular response to heat	IMP PMID:29949773 A PQM-1-Mediated Response Triggers Transcellular Chaperone S...	ACCEPT	Summary: DAF-21 is induced by heat stress in a PQM-1-dependent manner and is required for maintaining proteostasis under heat stress conditions. Reason: Strong experimental support for DAF-21 role in cellular response to heat through mutant phenotype analysis and expression studies. Supporting Evidence: PMID:29949773 We measured mRNA levels of a range of heat-inducible chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90
GO:0050821 protein stabilization	IMP PMID:29949773 A PQM-1-Mediated Response Triggers Transcellular Chaperone S...	ACCEPT	Summary: DAF-21 is required for protein stabilization and prevention of misfolding during cellular stress. Transcellular chaperone signaling activates DAF-21 to maintain proteostasis across tissues. Reason: Direct experimental evidence from mutant phenotype analysis demonstrating DAF-21 role in preventing protein misfolding. Supporting Evidence: PMID:29949773 Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Abeta3-42-associated toxicity
GO:0032991 protein-containing complex	IPI PMID:26593036 The activity of protein phosphatase 5 towards native clients...	ACCEPT	Summary: DAF-21 forms heterotetrameric complexes with PPH-5, with two PPH-5 molecules binding to the DAF-21 dimer. Complex formation demonstrated by analytical ultracentrifugation. Reason: Direct biophysical evidence for complex formation between DAF-21 and PPH-5 with defined stoichiometry. Supporting Evidence: PMID:26593036 This increase in absorption reflects the binding of two molecules of PPH-5 to the CeHsp90 dimer
GO:1990634 protein phosphatase 5 binding	IPI PMID:26593036 The activity of protein phosphatase 5 towards native clients...	ACCEPT	Summary: DAF-21 directly binds PPH-5 (protein phosphatase 5 ortholog) through its C-terminal MEEVD motif and additional interaction sites. This binding activates the phosphatase. Reason: Highly specific and informative annotation. Direct biochemical and biophysical evidence demonstrates this interaction. Supporting Evidence: PMID:26593036 The TPR domain is found in human PP5 and in its homologs from Saccharomyces cerevisiae (PPT1) and Caenorhabditis elegans (PPH-5)
GO:0032991 protein-containing complex	IDA PMID:26593036 The activity of protein phosphatase 5 towards native clients...	ACCEPT	Summary: Direct evidence for DAF-21 complex formation from analytical ultracentrifugation and SAXS experiments showing defined stoichiometry of Hsp90-PPH-5 complexes. Reason: Duplicate annotation for complex membership with direct experimental evidence. Accept both as they represent different evidence types. Supporting Evidence: PMID:26593036 A global fit confirms the stoichiometry and suggests a binding affinity in the range of 1 μM for the first and second PPH-5 molecule
GO:0035259 nuclear glucocorticoid receptor binding	IPI PMID:26593036 The activity of protein phosphatase 5 towards native clients...	KEEP AS NON CORE	Summary: DAF-21 was shown to bind the glucocorticoid receptor (GR) ligand binding domain in heterologous assays. Ternary complexes of DAF-21-PPH-5-GR were demonstrated. Reason: This annotation was derived from experiments using heterologous substrates (human GR) to study DAF-21 mechanism. While it demonstrates conserved HSP90 function, it does not represent a native C. elegans interaction. Keep as non-core since it reflects conserved biochemical properties. Supporting Evidence: PMID:26593036 ternary complexes with the glucocorticoid receptor (GR) are cooperatively formed by full-length Hsp90 and PPH-5
GO:0006611 protein export from nucleus	IMP PMID:23396260 Yes-associated protein homolog, YAP-1, is involved in the th...	KEEP AS NON CORE	Summary: DAF-21 regulates YAP-1 nuclear export after heat shock treatment. Knockdown of DAF-21 blocks the nuclear export of YAP-1 during recovery from heat stress. Reason: This is a specific downstream effect of DAF-21 chaperone activity on YAP-1 subcellular localization, rather than a core molecular function. Keep as non-core biological process. Supporting Evidence: PMID:23396260 Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery
GO:0006935 chemotaxis	IGI PMID:7828815 Multiple chemosensory defects in daf-11 and daf-21 mutants o...	KEEP AS NON CORE	Summary: daf-21 mutants show defects in chemotaxis to non-volatile and volatile attractants. This function is mediated through DAF-21 role in chemosensory signal transduction, likely by stabilizing DAF-11 guanylyl cyclase. Reason: Chemotaxis defects in daf-21 mutants reflect the requirement for DAF-21 in chemosensory neuron function, likely through client protein stabilization. This is a developmental/behavioral phenotype rather than core molecular function. Supporting Evidence: PMID:7828815 both mutants are defective in taxis to volatile attractants detected primarily by the amphid neuron AWC
GO:0050920 regulation of chemotaxis	IMP PMID:7828815 Multiple chemosensory defects in daf-11 and daf-21 mutants o...	KEEP AS NON CORE	Summary: daf-21 mutants show altered chemosensory behaviors, indicating a role in regulating chemotaxis through sensory signal transduction. Reason: This represents a phenotypic consequence of DAF-21 function in chemosensory neurons rather than a core molecular function. Keep as non-core. Supporting Evidence: PMID:7828815 daf-11 and daf-21 mutations were previously shown to cause inappropriate response to the dauer-inducing pheromone
GO:0005515 protein binding	IPI PMID:17610845 Cloning, expression and characterisation of FKB-6, the sole ...	MODIFY	Summary: Interaction with FKB-6, the large TPR-containing immunophilin in C. elegans. FKB-6 binds DAF-21 C-terminal MEEVD peptide via its TPR domain. Reason: Valid co-chaperone interaction. "Protein binding" is too general. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:17610845 Cloning, expression and characterisation of FKB-6, the sole large TPR-containing immunophilin from C.
GO:0005515 protein binding	IPI PMID:24012004 The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the prot...	MODIFY	Summary: Interaction with EBAX-1, a Cullin-RING E3 ligase component, demonstrating DAF-21 role in protein quality control of the SAX-3/Robo receptor. Reason: Valid interaction but "protein binding" is too vague. This interaction is in the context of protein quality control. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:24012004 The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons.
GO:0005515 protein binding	IPI PMID:16672054 Direct and heterologous approaches to identify the LET-756/F...	MODIFY	Summary: DAF-21 was identified as a LET-756/FGF interactor in a yeast two-hybrid screen. The interaction was validated by co-immunoprecipitation in mammalian cells, though with lower strength than other partners. Reason: The interaction with LET-756 (FGF) was detected in yeast two-hybrid and confirmed by co-immunoprecipitation. However, "protein binding" is too general for an HSP90 chaperone interaction. The authors note that HSP family members are sometimes considered false positives in Y2H screens. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:16672054 DAF-21, a chaperone of the HSP-90 family, involved in chemosensory transduction and insulin signalization
GO:0051604 protein maturation	NAS PMID:20880838 Cdc37-Hsp90 complexes are responsive to nucleotide-induced c...	ACCEPT	Summary: This annotation from ComplexPortal reflects DAF-21/HSP90 role in client protein maturation. The study characterized C. elegans Cdc37-Hsp90 complexes and their role in kinase client maturation. Reason: Protein maturation is a well-documented function of HSP90 chaperones, particularly in the context of kinase client activation. The NAS evidence is supported by direct biochemical studies of the C. elegans HSP90-CDC-37 complex. Supporting Evidence: PMID:20880838 Hsp90 is an ATP-dependent molecular chaperone, which facilitates the activation and stabilization of hundreds of client proteins in cooperation with a defined set of cofactors
GO:0045121 membrane raft	HDA PMID:21070894 An analysis of the Caenorhabditis elegans lipid raft proteom...	KEEP AS NON CORE	Summary: DAF-21 was identified in a proteomic analysis of C. elegans lipid raft fractions, suggesting some membrane raft association. Reason: Mass spectrometry identification in membrane raft fractions suggests some membrane association, but this is not the primary localization. Keep as non-core localization. Supporting Evidence: PMID:21070894 2010 Nov 8. An analysis of the Caenorhabditis elegans lipid raft proteome using geLC-MS/MS.
GO:0016887 ATP hydrolysis activity	IDA PMID:19559711 The non-canonical Hop protein from Caenorhabditis elegans ex...	ACCEPT	Summary: Direct biochemical measurement of DAF-21 ATPase activity and its regulation by co-chaperone STI-1 (Hop). Reason: Direct enzymatic assay demonstrating DAF-21 ATPase activity. This is a core molecular function of HSP90 proteins. Supporting Evidence: PMID:19559711 2009 Jun 25. The non-canonical Hop protein from Caenorhabditis elegans exerts essential functions and forms binary complexes with either Hsc70 or Hsp90.
GO:0002119 nematode larval development	IMP PMID:10790386 A transmembrane guanylyl cyclase (DAF-11) and Hsp90 (DAF-21)...	ACCEPT	Summary: daf-21 null mutants show early larval lethality, and hypomorphic mutants (E292K) have developmental defects. The gene is essential for larval development. Reason: daf-21 is essential for C. elegans development. Null mutants are lethal and hypomorphic mutants show developmental abnormalities. Supporting Evidence: PMID:10790386 daf-21 encodes the heat-shock protein 90 (Hsp90)
GO:0008340 determination of adult lifespan	IGI PMID:14668486 Regulation of longevity in Caenorhabditis elegans by heat sh...	KEEP AS NON CORE	Summary: DAF-21 functions in the insulin-like signaling pathway to regulate longevity. Downregulation of chaperones including DAF-21 decreases longevity of long-lived mutant animals. Reason: While DAF-21 contributes to lifespan regulation, this represents a downstream phenotypic consequence of chaperone function affecting proteostasis. Keep as non-core biological process. Supporting Evidence: PMID:14668486 Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals
GO:0005737 cytoplasm	IDA PMID:12950278 Caenorhabditis elegans DAF-21 (HSP90) is characteristically ...	ACCEPT	Summary: Direct immunolocalization of DAF-21 shows cytoplasmic distribution in C. elegans tissues, with enrichment in the perinuclear region. Reason: Experimental evidence from immunofluorescence studies confirms cytoplasmic localization of DAF-21. Supporting Evidence: PMID:12950278 Caenorhabditis elegans DAF-21 (HSP90) is characteristically and predominantly expressed in germline cells: spatial and temporal analysis.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:12950278 Caenorhabditis elegans DAF-21 (HSP90) is characteristically ...	ACCEPT	Summary: Direct immunolocalization showing DAF-21 enrichment in the perinuclear region of somatic cells. Reason: Direct experimental evidence for perinuclear localization. Supporting Evidence: PMID:12950278 Caenorhabditis elegans DAF-21 (HSP90) is characteristically and predominantly expressed in germline cells: spatial and temporal analysis.
GO:0040024 dauer larval development	IMP PMID:11677050 DAF-7/TGF-beta expression required for the normal larval dev...	ACCEPT	Summary: DAF-21 is required for proper dauer formation, the core phenotype that gave the gene its name. daf-21 mutants show dauer formation defects and act upstream of DAF-7/TGF-beta in the dauer pathway. Reason: Dauer formation is the defining phenotype for which daf-21 was named. This is a well-documented developmental role mediated through DAF-21 chaperone function on signal transduction components. Supporting Evidence: PMID:11677050 daf-11 gene and a related gene daf-21 act upstream of daf-7
GO:0040024 dauer larval development	IGI PMID:11677050 DAF-7/TGF-beta expression required for the normal larval dev...	ACCEPT	Summary: Genetic interaction between daf-21 and daf-11 in the dauer formation pathway. Both genes regulate DAF-7 expression and dauer development. Reason: Genetic interaction evidence supporting DAF-21 role in dauer formation pathway. Supporting Evidence: PMID:11677050 daf-11 gene and a related gene daf-21 act upstream of daf-7

Core Functions

DAF-21 is the sole C. elegans HSP90, an ATP-dependent molecular chaperone that promotes protein folding and stabilization of client proteins. Demonstrated through biochemical assays (ATPase activity, client binding) and genetic analysis (aggregation of myosin in knockdowns).

Molecular Function:

ATP-dependent protein folding chaperone

DAF-21 directly activates PPH-5 phosphatase activity through binding to its TPR domain and additional interaction sites. Demonstrated through biochemical assays (PMID:26593036).

Molecular Function:

protein phosphatase activator activity

Core HSP90 molecular function as chaperone. DAF-21 binds unfolded or misfolded client proteins to facilitate their proper folding or targeting for degradation.

Molecular Function:

protein folding chaperone

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

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

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:7828815

Multiple chemosensory defects in daf-11 and daf-21 mutants of Caenorhabditis elegans.

daf-21 mutants are defective in chemotaxis to non-volatile and volatile attractants

"both mutants are defective in taxis to volatile attractants detected primarily by the amphid neuron AWC"
DAF-21 may mediate sensory transduction for specific chemosensory pathways

"daf-11 and daf-21 mutations were previously shown to cause inappropriate response to the dauer-inducing pheromone"

PMID:10790386

A transmembrane guanylyl cyclase (DAF-11) and Hsp90 (DAF-21) regulate a common set of chemosensory behaviors in caenorhabditis elegans.

daf-21 encodes the C. elegans HSP90 ortholog

"daf-21 encodes the heat-shock protein 90 (Hsp90)"

PMID:11677050

DAF-7/TGF-beta expression required for the normal larval development in C. elegans is controlled by a presumed guanylyl cyclase DAF-11.

daf-11 and daf-21 act upstream of daf-7 in dauer pathway

"daf-11 gene and a related gene daf-21 act upstream of daf-7"

PMID:11809970

Role of the myosin assembly protein UNC-45 as a molecular chaperone for myosin.

UNC-45 TPR domain binds HSP90

"The amino-terminal tetratricopeptide repeat domain of UNC-45 bound the molecular chaperone Hsp90"

PMID:12950278

Caenorhabditis elegans DAF-21 (HSP90) is characteristically and predominantly expressed in germline cells: spatial and temporal analysis.

DAF-21 is localized to perinuclear region of somatic cells

"the DAF-21 protein seemed to be localized in the perinuclear region of somatic cells"

PMID:14668486

Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones.

HSF-1 and molecular chaperones regulate longevity

"Down-regulation of individual molecular chaperones, transcriptional targets of HSF-1, also decreased longevity of long-lived mutant but not wild-type animals"

PMID:14992718

Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-beta signaling network.

DAF-21 interacts with DAF-1 TGF-beta receptor

"Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-beta pathway components defined a network of 71 interactions among 59 proteins"

PMID:16916933

Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity.

HSF-1 pathway requires 90-kDa inducible heat shock proteins for immunity

"The HSF-1 defense response is independent of the p38 MAPK/PMK-1 pathway and requires a system of chaperones including small and 90-kDa inducible HS proteins"

PMID:17610845

Cloning, expression and characterisation of FKB-6, the sole large TPR-containing immunophilin from C. elegans.

FKB-6 TPR domain interacts with DAF-21 C-terminal MEEVD peptide

"NMR studies of the interaction between FKB-6 and the C-terminal DAF-21 pentapeptide MEEVD"

PMID:19467242

C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and stress response.

STI-1 binds both Hsp70 and DAF-21/Hsp90

"CeSTI-1 can bind with both Hsp70 and Hsp90 homologs"

PMID:19559711

The non-canonical Hop protein from Caenorhabditis elegans exerts essential functions and forms binary complexes with either Hsc70 or Hsp90.

C. elegans Hop/STI-1 forms binary complexes with DAF-21

"forms binary complexes with either Hsc70 or Hsp90"
DAF-21 ATPase activity is inhibited by Hop binding

"inhibition of the Hsp90 ATPase activity can be observed upon binding of CeHop"

PMID:21070894

An analysis of the Caenorhabditis elegans lipid raft proteome using geLC-MS/MS.

DAF-21 identified in lipid raft proteome

"A study of the lipid raft proteome of C. elegans is presented here"

PMID:21980476

Downregulation of the Hsp90 system causes defects in muscle cells of Caenorhabditis elegans.

DAF-21 is required for proper myosin localization in muscle

"aggregates of the myosin MYO-3 are visible in muscle cells, if DAF-21 is depleted, implying a role of Hsp90 in the maintenance of muscle cell functionality"
daf-21(p673) E292K mutant has reduced ATPase activity

"At 30°C, the ATPase activity of E292K-DAF-21 was found to be 0.1 min−1, while that of wt-DAF-21 was 0.6 min−1 (Figure 1B)"

PMID:23332754

The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans.

UNC-45 interacts with DAF-21 during myofilament formation

"For Hsp90 (DAF-21 in C. elegans)"

PMID:23396260

Yes-associated protein homolog, YAP-1, is involved in the thermotolerance and aging in the nematode Caenorhabditis elegans.

DAF-21 regulates YAP-1 nuclear export after heat shock

"Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery"

PMID:23746847

Regulation of organismal proteostasis by transcellular chaperone signaling.

HSP-90 expression in one tissue induces systemic stress response

"elevated expression of HSP90 in intestine or neuronal cells"

PMID:24012004

The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons.

DAF-21 interacts with EBAX-1 for protein quality control

"EBAX-1 also binds to DAF-21, a cytosolic Hsp90 chaperone"

PMID:26593036

The activity of protein phosphatase 5 towards native clients is modulated by the middle- and C-terminal domains of Hsp90.

DAF-21 binds and activates PPH-5 phosphatase

"we observed an increase of the phosphatase activity in the presence of C. elegans Hsp90 (CeHsp90)"
Two PPH-5 molecules bind per DAF-21 dimer

"This increase in absorption reflects the binding of two molecules of PPH-5 to the CeHsp90 dimer"
Ternary complexes form with glucocorticoid receptor as client

"ternary complexes with the glucocorticoid receptor (GR) are cooperatively formed by full-length Hsp90 and PPH-5"

PMID:29949773

A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.

DAF-21 is induced by heat stress in pqm-1-dependent manner

"We measured mRNA levels of a range of heat-inducible chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90"
DAF-21 prevents protein misfolding and maintains proteostasis

"Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Abeta3-42-associated toxicity"

PMID:16672054

Direct and heterologous approaches to identify the LET-756/FGF interactome.

DAF-21 interacts with LET-756/FGF in yeast two-hybrid screen

"DAF-21, a chaperone of the HSP-90 family"

PMID:20880838

Cdc37-Hsp90 complexes are responsive to nucleotide-induced conformational changes and binding of further cofactors.

C. elegans Hsp90 forms complexes with Cdc37 for kinase client processing

"Hsp90 is an ATP-dependent molecular chaperone, which facilitates the activation and stabilization of hundreds of client proteins"

file:worm/daf-21/daf-21-deep-research-falcon.md

Deep research report on daf-21

Suggested Experiments

Experiment: Identify native DAF-21 client proteins by AP-MS. While some clients are known (DAF-11, WEE-1.3), a systematic identification of native DAF-21 clients in C. elegans would clarify its cellular roles.

Hypothesis: DAF-21 interacts with multiple signal transduction proteins beyond DAF-11

Experiment: Determine tissue-specific requirements for DAF-21 using tissue-specific RNAi. Understanding which tissues require DAF-21 for viability and specific phenotypes would clarify its developmental roles.

Hypothesis: DAF-21 is required in multiple tissues for different aspects of development

📚 Additional Documentation

Deep Research Falcon

(daf-21-deep-research-falcon.md)

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organism_full: Caenorhabditis elegans.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q18688
Protein Description: RecName: Full=Heat shock protein 90; AltName: Full=Abnormal dauer formation protein 21;
Gene Information: Name=hsp-90 {ECO:0000312|EMBL:CAA99793.1}; Synonyms=daf-21 {ECO:0000312|EMBL:CAA99793.1}; ORFNames=C47E8.5;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the heat shock protein 90 family. .
Key Domains: HATPase_C_sf. (IPR036890); HSP90_C. (IPR037196); Hsp90_fam. (IPR001404); Hsp90_N. (IPR020575); Ribosomal_Su5_D2-typ_SF. (IPR020568)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-90" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'hsp-90' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene hsp-90 (gene ID: daf-21, UniProt: Q18688) in worm.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q18688
Protein Description: RecName: Full=Heat shock protein 90; AltName: Full=Abnormal dauer formation protein 21;
Gene Information: Name=hsp-90 {ECO:0000312|EMBL:CAA99793.1}; Synonyms=daf-21 {ECO:0000312|EMBL:CAA99793.1}; ORFNames=C47E8.5;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the heat shock protein 90 family. .
Key Domains: HATPase_C_sf. (IPR036890); HSP90_C. (IPR037196); Hsp90_fam. (IPR001404); Hsp90_N. (IPR020575); Ribosomal_Su5_D2-typ_SF. (IPR020568)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "hsp-90" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene hsp-90 (gene ID: daf-21, UniProt: Q18688) in worm.

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.

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.

Plan and verification
- Identity check: The target is Caenorhabditis elegans hsp-90 (synonym daf-21; ORF C47E8.5), encoding the single cytosolic Hsp90 isoform. Literature explicitly states C. elegans has one cytosolic HSP-90/DAF-21 and aligns with canonical Hsp90 domains and ATPase cycle, matching UniProt Q18688 (Hsp90_N, middle domain with catalytic glutamate, charged linker, C-terminal dimerization with MEEVD) (oostenhawle2023organismalrolesofa pages 1-3, gaiser2011downregulationofthe pages 14-14).

Comprehensive research report on C. elegans hsp-90/daf-21 (UniProt Q18688)

1) Key concepts and definitions
- Molecular identity and family: DAF-21/HSP-90 is the sole cytosolic Hsp90 in C. elegans, a highly conserved ATP-dependent molecular chaperone that assists folding/activation of many signaling clients (kinases, transcription factors, steroid receptors) (Biomolecules review, Jan 2023, https://doi.org/10.3390/biom13020251) (oostenhawle2023organismalrolesofa pages 1-3, oostenhawle2023organismalrolesof pages 5-7).
- ATPase cycle and conformational switching: HSP-90 operates as a dimer; ATP binding drives N-terminal dimerization and a closed conformation stabilized by p23/Sba1, hydrolysis promotes client release and reopening; cycle kinetics are tuned by cochaperones such as Aha1 (accelerates ATPase) and Cdc37 (kinase loading) (reviewed 2023; structural/mechanistic citations within the C. elegans studies) (oostenhawle2023organismalrolesofa pages 1-3, gaiser2011downregulationofthe pages 14-14).
- C. elegans biochemical properties: DAF-21 exhibits chaperone activity suppressing thermal aggregation of client reporters (citrate synthase) in vitro; YFP tagging reduces ATP hydrolysis but ATPase is stimulated by C. elegans Aha1 (CeAha1). Analytical ultracentrifugation shows DAF-21 at ~5.9 S, with cofactor-induced complex shifts, consistent with nucleotide- and partner-dependent conformational states (PLoS ONE, Sep 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).

2) Recent developments and latest research (emphasis 2023–2024)
- Organismal proteostasis signaling and longevity: In metazoans including C. elegans, HSP-90 regulates inter-tissue proteostasis programs. Overexpression or depletion can trigger transcellular chaperone signaling (TCS) between gut, neurons, and muscle via PQM-1 and tissue-specific secreted mediators; mild pharmacologic HSP90 inhibition (e.g., tanespimycin/monorden) can extend lifespan via HSF-1, whereas strong depletion causes developmental defects (Biomolecules review, Jan 2023, https://doi.org/10.3390/biom13020251) (oostenhawle2023organismalrolesof pages 5-7).
- Transcriptomic arrest state mapping after hsp-90 RNAi: Genome-wide coexpression clique analysis (Scientific Reports, Jun 2021, https://doi.org/10.1038/s41598-021-91690-6) showed that hsp-90/daf-21 RNAi arrests development near the L4 stage with characteristic induction of heat-shock response and alterations in innate immune and DAF-16 target gene cliques; L4 correspondence was supported by correlation coefficients R² ≈ 0.40–0.59 across datasets (schmauder2021hsp90andunc45 pages 1-2, schmauder2021hsp90andunc45 pages 9-10).
- Neuron/cilia-specific client control (new): A 2025 G3 study reported an hsp-90/daf-21 missense allele (S564F) that causes misaccumulation of endogenous GFP::DLK-1 and up-regulates CEBP-1 specifically in ciliated sensory neurons, linking HSP-90 to cilia/intraflagellar transport-regulated DLK-1 signaling (Advance Access Jan 24, 2025, https://doi.org/10.1093/g3journal/jkaf004) (sun2025multipleregulatorsconstrain pages 1-2, sun2025multipleregulatorsconstrain pages 8-12).

3) Current applications and real-world implementations
- Genetic perturbations: Tissue-specific RNAi and hypomorphic alleles are used to resolve daf-21 roles by stage and tissue, revealing spatiotemporal requirements in development, fertility, and longevity, including neuron-specific contributions to dauer induction (Scientific Reports, Aug 2018, https://doi.org/10.1038/s41598-018-30592-6) (somogyvari2018daf21hsp90isrequired pages 8-10).
- Pharmacology: Classical HSP90 inhibitors (e.g., geldanamycin, radicicol; also tanespimycin/monorden) are used in worms to modulate HSP90, with dose-dependent organismal effects on lifespan and stress responses (Biomolecules review, 2023, https://doi.org/10.3390/biom13020251) (oostenhawle2023organismalrolesof pages 5-7).
- Biophysical interaction assays in vivo: YFP-DAF-21 localization and mobility, and interaction with muscle co-chaperone UNC-45, have been leveraged to map muscle assembly roles; fluorescence/AUC approaches quantify binding to TPR co-chaperones (UNC-45N, PPH-5, STI-1) (PLoS ONE, 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).

4) Expert opinions and analysis from authoritative sources
- Review perspective: HSP-90 integrates intracellular proteostasis with organismal stress signaling, impacting development, immunity, neuronal function, behavior, aging, and evolution; C. elegans provides a single cytosolic HSP-90/DAF-21 enabling clear genetic dissection (Biomolecules, 2023, https://doi.org/10.3390/biom13020251) (oostenhawle2023organismalrolesofa pages 1-3, oostenhawle2023organismalrolesof pages 5-7).
- Systems-level transcriptomics: Coexpression clique analysis offers a rigorous map of hsp-90 RNAi developmental arrest and ties HSP-90 depletion to DAF-16-regulated deviations from normal developmental programs (Scientific Reports, 2021, https://doi.org/10.1038/s41598-021-91690-6) (schmauder2021hsp90andunc45 pages 9-10, schmauder2021hsp90andunc45 pages 19-20).

5) Relevant statistics and data from recent studies
- Biophysical/enzymatic: DAF-21 suppresses citrate synthase aggregation at 0.1 mM (partial) and 0.5 mM (full) in vitro; sedimentation ~5.9 S for DAF-21, shifting to ~6.7 S with UNC-45N, and YFP-DAF-21 ~7.3 S shifting to ~6.0 S upon intramolecular fragment addition; ATPase stimulation by CeAha1 is demonstrable (PLoS ONE, 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).
- Developmental mapping: hsp-90 RNAi-arrested state correlates best with L4 (R² ≈ 0.4046, 0.5913, 0.5915 across datasets); clique-level enrichments cover cuticle/collagen, dauer metabolism, and reproductive phenotypes (Scientific Reports, 2021, https://doi.org/10.1038/s41598-021-91690-6) (schmauder2021hsp90andunc45 pages 9-10, schmauder2021hsp90andunc45 pages 14-15).
- Longevity modulation: daf-21 knockdown shortens wild-type and daf-2 mutant lifespan and selectively impairs DAF-16A-driven longevity programs, while leaving DAF-16D/F largely unaffected; DAF-21 promotes DAF-16A nuclear translocation and target gene induction under IIS reduction and heat shock (Scientific Reports, Aug 2018, https://doi.org/10.1038/s41598-018-30592-6) (somogyvari2018daf21hsp90isrequired pages 1-2, somogyvari2018daf21hsp90isrequired pages 8-10).

Functional annotation
- Molecular function and domains: DAF-21 is an ATP-dependent chaperone with canonical Hsp90 N-terminal nucleotide-binding domain, middle domain harboring catalytic Glu and client-contact surfaces, flexible charged linker, and C-terminal dimerization domain with MEEVD motif for TPR cochaperone binding. Its ATPase cycle undergoes nucleotide-dependent N-terminal dimerization and p23-stabilized closure, with cochaperones Aha1 (activates ATP hydrolysis) and Cdc37 (stabilizes kinase clients) modulating kinetics and client flow (Biomolecules 2023; PLoS ONE 2011) (oostenhawle2023organismalrolesofa pages 1-3, gaiser2011downregulationofthe pages 14-14, gaiser2011downregulationofthe pages 13-13).
- Principal co-chaperones in C. elegans: Interactions have been observed with TPR co-chaperones UNC-45 (muscle myosin assembly), PPH-5, and STI-1/HOP via fluorescence-detection AUC; Aha1 stimulates DAF-21 ATPase; p23 stabilizes the closed ATP-bound state; Cdc37 (p50) mediates kinase client loading; PPIase FKB-6 stabilizes kinase–Hsp90 complexes in metazoa with worm-relevant implications (PLoS ONE 2011; review/thesis synthesis of C. elegans system) (gaiser2011downregulationofthe pages 13-13, schmauder2022regulationandmechanistical pages 139-141, gaiser2011downregulationofthe pages 14-14).
- Known clients/pathways in C. elegans:
• DAF-16/FOXO pathway: DAF-21 promotes DAF-16A activation and nuclear translocation under reduced IIS and heat shock, enabling DAF-16A-specific transcription and lifespan extension; effects on DAF-16D/F are minimal (Scientific Reports 2018, https://doi.org/10.1038/s41598-018-30592-6) (somogyvari2018daf21hsp90isrequired pages 1-2, somogyvari2018daf21hsp90isrequired pages 8-10).
• Muscle myosin assembly: DAF-21 cooperates with UNC-45; its depletion causes MYO-3 aggregation and motility defects, evidencing client roles in sarcomere proteostasis (PLoS ONE 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).
• DLK-1–CEBP-1 signaling in ciliated neurons: hsp-90(S564F) increases DLK-1 abundance at cilia and elevates CEBP-1, revealing a neuron/cilia-specific client relationship (G3 2025, https://doi.org/10.1093/g3journal/jkaf004) (sun2025multipleregulatorsconstrain pages 1-2, sun2025multipleregulatorsconstrain pages 8-12).
• Dauer formation and chemosensation: daf-21 influences dauer entry and chemosensory pathways linked to DAF-11 guanylyl cyclase and TGF-β/DAF-7 signaling network components, situating HSP-90 in developmental and sensory signaling (Biomolecules 2023) (oostenhawle2023organismalrolesofa pages 10-11).
• Potential steroid receptor axis: p23–Hsp90 complex impacts longevity in a temperature-dependent manner; DAF-12 has been noted as an Hsp90/p23-related client in nematodes, suggesting roles in nuclear receptor maturation (Biomolecules 2023) (oostenhawle2023organismalrolesof pages 5-7).

Subcellular localization
- Muscle: YFP-DAF-21 localizes to I-band and M-line in live muscle but is transient and not stably attached to myofilaments, consistent with a diffusible chaperone role in sarcomere maintenance; UNC-45 shows broader and more stable myofilament association (PLoS ONE, 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).
- Neurons/cilia: The hsp-90(S564F) allele shows a cilia-enriched effect on DLK-1 accumulation, indicating cilia-compartment regulation; HSP-90 is broadly expressed but can have compartment-specific impacts (G3, 2025, https://doi.org/10.1093/g3journal/jkaf004) (sun2025multipleregulatorsconstrain pages 8-12).

Phenotypes of loss-of-function, RNAi, hypomorphs, and chemical inhibition
- Strong reduction (RNAi/hypomorph): Developmental arrest near L4 stage, reduced motility, heat-shock/innate immune transcriptome activation, and reproductive defects including impaired oocyte development; essential for vulva/gonad development and oocyte meiotic transitions (Scientific Reports 2021, https://doi.org/10.1038/s41598-021-91690-6; Biomolecules 2023) (schmauder2021hsp90andunc45 pages 1-2, schmauder2021hsp90andunc45 pages 11-12, oostenhawle2023organismalrolesofa pages 10-11).
- Muscle-specific outcomes: MYO-3 aggregation, induction of muscle stress responses, and motility defects upon DAF-21 depletion or ATPase-compromised alleles (PLoS ONE, 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).
- Longevity modulation: daf-21 knockdown shortens lifespan and suppresses DAF-16A-dependent longevity; neuronal daf-21 silencing contributes to dauer induction under specific contexts (Scientific Reports, 2018, https://doi.org/10.1038/s41598-018-30592-6) (somogyvari2018daf21hsp90isrequired pages 8-10).
- Pharmacologic modulation: Mild HSP90 inhibition extends lifespan via HSF-1; conversely, severe inhibition is detrimental to development and viability (Biomolecules, 2023, https://doi.org/10.3390/biom13020251) (oostenhawle2023organismalrolesof pages 5-7).

Pathways and mechanistic context
- Insulin/IGF-1–DAF-2/DAF-16 axis: DAF-21 regulates DAF-16A activation and nuclear translocation downstream of insulin receptor signaling and heat shock, integrating proteostasis with stress and metabolic control of longevity (Scientific Reports 2018, https://doi.org/10.1038/s41598-018-30592-6) (somogyvari2018daf21hsp90isrequired pages 1-2, somogyvari2018daf21hsp90isrequired pages 8-10).
- TGF-β/DAF-7 and chemosensory networks: HSP-90 intersects with dauer and sensory signaling networks (e.g., DAF-11), consistent with broad client coverage of signaling components (Biomolecules, 2023) (oostenhawle2023organismalrolesofa pages 10-11).
- Muscle proteostasis pathway: DAF-21 cooperates with UNC-45 and other TPR co-chaperones to maintain sarcomere integrity, aligning with localization and aggregation phenotypes (PLoS ONE, 2011, https://doi.org/10.1371/journal.pone.0025485) (gaiser2011downregulationofthe pages 13-13).
- Neuronal/ciliary stress signaling: New evidence ties HSP-90 to DLK-1–CEBP-1 regulation in ciliated sensory neurons, integrating Hsp90 with axon/dendrite compartmental quality control and intraflagellar transport (G3, 2025, https://doi.org/10.1093/g3journal/jkaf004) (sun2025multipleregulatorsconstrain pages 1-2, sun2025multipleregulatorsconstrain pages 8-12).

Limitations and open questions
- Quantitative lifespan effects of graded daf-21 perturbations can vary by timing and tissue; many numerical values are context-dependent and not uniformly reported across studies. Client catalogs in C. elegans remain incomplete; recent work nominates neuron/cilia clients (DLK-1) and muscle clients (myosins), with broader signaling targets inferred from conserved Hsp90 biology (somogyvari2018daf21hsp90isrequired pages 1-2, oostenhawle2023organismalrolesof pages 5-7, sun2025multipleregulatorsconstrain pages 1-2).

References with URLs and dates
- van Oosten-Hawle P. Organismal roles of Hsp90. Biomolecules. 2023 Jan;13:251. https://doi.org/10.3390/biom13020251 (oostenhawle2023organismalrolesofa pages 1-3, oostenhawle2023organismalrolesof pages 5-7, oostenhawle2023organismalrolesofa pages 10-11).
- Schmauder L, Richter K. hsp-90 and unc-45 depletion induce transcriptional signatures in coexpression cliques of C. elegans. Scientific Reports. 2021 Jun;11: https://doi.org/10.1038/s41598-021-91690-6 (schmauder2021hsp90andunc45 pages 1-2, schmauder2021hsp90andunc45 pages 14-15, schmauder2021hsp90andunc45 pages 9-10, schmauder2021hsp90andunc45 pages 19-20, schmauder2021hsp90andunc45 pages 11-12).
- Somogyvári M, Gecse E, Sőti C. DAF-21/Hsp90 is required for C. elegans longevity by ensuring DAF-16/FOXO isoform A function. Scientific Reports. 2018 Aug;8: https://doi.org/10.1038/s41598-018-30592-6 (somogyvari2018daf21hsp90isrequired pages 1-2, somogyvari2018daf21hsp90isrequired pages 8-10).
- Gaiser AM, Kaiser CJO, Haslbeck V, Richter K. Downregulation of the Hsp90 system causes defects in muscle cells of C. elegans. PLoS ONE. 2011 Sep;6:e25485. https://doi.org/10.1371/journal.pone.0025485 (gaiser2011downregulationofthe pages 13-13, gaiser2011downregulationofthe pages 14-14).
- Sun Y et al. Multiple regulators constrain the abundance of C. elegans DLK-1 in ciliated sensory neurons. G3. Advance Access 2025 Jan 24. https://doi.org/10.1093/g3journal/jkaf004 (sun2025multipleregulatorsconstrain pages 1-2, sun2025multipleregulatorsconstrain pages 8-12).

References

(oostenhawle2023organismalrolesofa pages 1-3): P van Oosten-Hawle. Organismal roles of hsp90. biomolecules 2023, 13, 251. Unknown journal, 2023.
(gaiser2011downregulationofthe pages 14-14): Andreas M. Gaiser, Christoph J. O. Kaiser, Veronika Haslbeck, and Klaus Richter. Downregulation of the hsp90 system causes defects in muscle cells of caenorhabditis elegans. PLoS ONE, 6:e25485, Sep 2011. URL: https://doi.org/10.1371/journal.pone.0025485, doi:10.1371/journal.pone.0025485. This article has 82 citations and is from a peer-reviewed journal.
(oostenhawle2023organismalrolesof pages 5-7): Patricija van Oosten-Hawle. Organismal roles of hsp90. Biomolecules, 13:251, Jan 2023. URL: https://doi.org/10.3390/biom13020251, doi:10.3390/biom13020251. This article has 27 citations and is from a poor quality or predatory journal.
(gaiser2011downregulationofthe pages 13-13): Andreas M. Gaiser, Christoph J. O. Kaiser, Veronika Haslbeck, and Klaus Richter. Downregulation of the hsp90 system causes defects in muscle cells of caenorhabditis elegans. PLoS ONE, 6:e25485, Sep 2011. URL: https://doi.org/10.1371/journal.pone.0025485, doi:10.1371/journal.pone.0025485. This article has 82 citations and is from a peer-reviewed journal.
(schmauder2021hsp90andunc45 pages 1-2): Lukas Schmauder and Klaus Richter. Hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of c. elegans. Scientific Reports, Jun 2021. URL: https://doi.org/10.1038/s41598-021-91690-6, doi:10.1038/s41598-021-91690-6. This article has 5 citations and is from a peer-reviewed journal.
(schmauder2021hsp90andunc45 pages 9-10): Lukas Schmauder and Klaus Richter. Hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of c. elegans. Scientific Reports, Jun 2021. URL: https://doi.org/10.1038/s41598-021-91690-6, doi:10.1038/s41598-021-91690-6. This article has 5 citations and is from a peer-reviewed journal.
(sun2025multipleregulatorsconstrain pages 1-2): Yue Sun, Junxiang Zhou, Arunima Debnath, Bokun Xie, Zhiping Wang, and Yishi Jin. Multiple regulators constrain the abundance of caenorhabditis elegans dlk-1 in ciliated sensory neurons. G3: Genes | Genomes | Genetics, Jan 2025. URL: https://doi.org/10.1093/g3journal/jkaf004, doi:10.1093/g3journal/jkaf004. This article has 0 citations.
(sun2025multipleregulatorsconstrain pages 8-12): Yue Sun, Junxiang Zhou, Arunima Debnath, Bokun Xie, Zhiping Wang, and Yishi Jin. Multiple regulators constrain the abundance of caenorhabditis elegans dlk-1 in ciliated sensory neurons. G3: Genes | Genomes | Genetics, Jan 2025. URL: https://doi.org/10.1093/g3journal/jkaf004, doi:10.1093/g3journal/jkaf004. This article has 0 citations.
(somogyvari2018daf21hsp90isrequired pages 8-10): Milán Somogyvári, Eszter Gecse, and Csaba Sőti. Daf-21/hsp90 is required for c. elegans longevity by ensuring daf-16/foxo isoform a function. Scientific Reports, Aug 2018. URL: https://doi.org/10.1038/s41598-018-30592-6, doi:10.1038/s41598-018-30592-6. This article has 41 citations and is from a peer-reviewed journal.
(schmauder2021hsp90andunc45 pages 19-20): Lukas Schmauder and Klaus Richter. Hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of c. elegans. Scientific Reports, Jun 2021. URL: https://doi.org/10.1038/s41598-021-91690-6, doi:10.1038/s41598-021-91690-6. This article has 5 citations and is from a peer-reviewed journal.
(schmauder2021hsp90andunc45 pages 14-15): Lukas Schmauder and Klaus Richter. Hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of c. elegans. Scientific Reports, Jun 2021. URL: https://doi.org/10.1038/s41598-021-91690-6, doi:10.1038/s41598-021-91690-6. This article has 5 citations and is from a peer-reviewed journal.
(somogyvari2018daf21hsp90isrequired pages 1-2): Milán Somogyvári, Eszter Gecse, and Csaba Sőti. Daf-21/hsp90 is required for c. elegans longevity by ensuring daf-16/foxo isoform a function. Scientific Reports, Aug 2018. URL: https://doi.org/10.1038/s41598-018-30592-6, doi:10.1038/s41598-018-30592-6. This article has 41 citations and is from a peer-reviewed journal.
(schmauder2022regulationandmechanistical pages 139-141): LM Schmauder. Regulation and mechanistical interplay of the hsp-90 and hsc-70 chaperone systems in caenorhabditis elegans. Unknown journal, 2022.
(oostenhawle2023organismalrolesofa pages 10-11): P van Oosten-Hawle. Organismal roles of hsp90. biomolecules 2023, 13, 251. Unknown journal, 2023.
(schmauder2021hsp90andunc45 pages 11-12): Lukas Schmauder and Klaus Richter. Hsp-90 and unc-45 depletion induce characteristic transcriptional signatures in coexpression cliques of c. elegans. Scientific Reports, Jun 2021. URL: https://doi.org/10.1038/s41598-021-91690-6, doi:10.1038/s41598-021-91690-6. This article has 5 citations and is from a peer-reviewed journal.

Citations

gaiser2011downregulationofthe pages 13-13
oostenhawle2023organismalrolesof pages 5-7
oostenhawle2023organismalrolesofa pages 10-11
sun2025multipleregulatorsconstrain pages 8-12
oostenhawle2023organismalrolesofa pages 1-3
gaiser2011downregulationofthe pages 14-14
sun2025multipleregulatorsconstrain pages 1-2
schmauder2022regulationandmechanistical pages 139-141
https://doi.org/10.3390/biom13020251
https://doi.org/10.1371/journal.pone.0025485
https://doi.org/10.1038/s41598-021-91690-6
https://doi.org/10.1093/g3journal/jkaf004
https://doi.org/10.1038/s41598-018-30592-6
https://doi.org/10.1038/s41598-021-91690-6;
https://doi.org/10.1371/journal.pone.0025485,
https://doi.org/10.3390/biom13020251,
https://doi.org/10.1038/s41598-021-91690-6,
https://doi.org/10.1093/g3journal/jkaf004,
https://doi.org/10.1038/s41598-018-30592-6,

📄 View Raw YAML

id: Q18688
gene_symbol: daf-21
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: DAF-21 is the sole HSP90 ortholog in C. elegans, functioning as an 
  essential ATP-dependent molecular chaperone critical for protein folding, 
  signal transduction, and stress response. The protein is required for multiple
  developmental processes including dauer formation (hence the "daf" 
  nomenclature), chemosensory behaviors, oocyte maturation, and muscle 
  maintenance. DAF-21 stabilizes client proteins including guanylyl cyclase 
  DAF-11 in chemosensory neurons, WEE-1.3 kinase during oocyte development, and 
  myosin in muscle cells. The chaperone functions in complexes with 
  co-chaperones including UNC-45, STI-1, CDC-37, and AHA-1, and activates 
  protein phosphatase 5 (PPH-5). DAF-21 also participates in transcellular 
  chaperone signaling, where tissue-specific HSP-90 expression can 
  non-cell-autonomously induce chaperone expression in distal tissues to 
  maintain organismal proteostasis.
existing_annotations:
  - term:
      id: GO:0006457
      label: protein folding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21/HSP90 is a well-established molecular chaperone that 
        promotes protein folding. This core function is supported by multiple 
        lines of evidence including the role in myosin folding in muscle cells 
        (PMID:21980476) and stabilization of client proteins such as DAF-11 
        guanylyl cyclase (PMID:10790386).
      action: ACCEPT
      reason: Protein folding is the central molecular function of HSP90 
        proteins. The phylogenetic inference from IBA is fully consistent with 
        experimental evidence showing DAF-21 participates in folding of myosin 
        and other client proteins.
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: The dimeric molecular chaperone Hsp90 is an 
            ATP-dependent cellular machine, which contributes to the activation 
            and regulation of steroid receptors, protein kinases and several 
            transcription factors
        - reference_id: PMID:10790386
          supporting_text: daf-21 encodes the heat-shock protein 90 (Hsp90)
        - reference_id: file:worm/daf-21/daf-21-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21 has been directly shown to possess ATPase activity. The 
        E292K mutation (daf-21(p673)) reduces ATPase activity compared to 
        wild-type (PMID:21980476), confirming ATP hydrolysis is integral to 
        DAF-21 function.
      action: ACCEPT
      reason: ATPase activity is a core enzymatic function of HSP90 proteins. 
        Direct biochemical measurement confirms DAF-21 hydrolyzes ATP, and this 
        activity is essential for chaperone function.
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: "At 30°C, the ATPase activity of E292K-DAF-21 was found
            to be 0.1 min−1, while that of wt-DAF-21 was 0.6 min−1 (Figure 1B)"
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21 functions as a homodimer and forms multi-protein chaperone
        complexes with co-chaperones including CDC-37, STI-1, PPH-5, and UNC-45.
        The protein forms defined complexes with co-chaperones as demonstrated 
        by analytical ultracentrifugation.
      action: ACCEPT
      reason: HSP90 functioning in multi-protein complexes is a well-established
        core feature. Multiple publications document specific complexes 
        containing DAF-21 with defined co-chaperones.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: This increase in absorption reflects the binding of 
            two molecules of PPH-5 to the CeHsp90 dimer
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: While IBA inference suggests plasma membrane localization based 
        on orthologs, direct evidence for DAF-21 localization in C. elegans 
        primarily shows cytoplasmic and perinuclear localization rather than 
        plasma membrane association.
      action: KEEP_AS_NON_CORE
      reason: The experimental evidence in C. elegans (PMID:12950278, 
        PMID:21980476) shows cytoplasmic localization with enrichment in the 
        perinuclear region. Membrane raft localization was detected by mass 
        spectrometry (PMID:21070894) suggesting some membrane association, but 
        this is not a primary localization site.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ATP binding is a fundamental property of HSP90 proteins required 
        for the chaperone cycle. The crystal structure (PDB:4GQT) shows the 
        N-terminal ATP binding domain of DAF-21, and functional studies confirm 
        nucleotide-dependent conformational changes.
      action: ACCEPT
      reason: ATP binding is essential for HSP90 chaperone function. Direct 
        structural evidence from X-ray crystallography confirms the ATP binding 
        domain, and functional studies demonstrate nucleotide-dependent 
        behaviors.
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: The functionality of DAF-21 is confirmed by its 
            ability to bind the cofactor Cep23, which specifically recognizes 
            the hydrolysis competent state with closed N-terminal domains
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21 is localized to the cytoplasm based on immunolocalization 
        studies. The protein shows predominantly cytoplasmic distribution with 
        perinuclear enrichment.
      action: ACCEPT
      reason: Cytoplasmic/cytosolic localization is consistent with the known 
        biology of HSP90 as a cytosolic chaperone and directly supported by 
        experimental evidence in C. elegans.
  - term:
      id: GO:0050821
      label: protein stabilization
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21 stabilizes client proteins including DAF-11 guanylyl 
        cyclase (required for chemosensory signaling) and WEE-1.3 kinase 
        (required for cell cycle control in oocytes). This is a core chaperone 
        function.
      action: ACCEPT
      reason: Protein stabilization is a core HSP90 function. Multiple 
        experimental studies in C. elegans demonstrate DAF-21 stabilizes 
        specific client proteins.
      supported_by:
        - reference_id: PMID:10790386
          supporting_text: daf-21 encodes the heat-shock protein 90 (Hsp90)
  - term:
      id: GO:0034605
      label: cellular response to heat
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: DAF-21 plays a critical role in cellular response to heat stress.
        The protein is part of the HSF-1 pathway required for thermotolerance.
      action: ACCEPT
      reason: Response to heat is a well-documented function of HSP90 proteins. 
        Multiple C. elegans studies demonstrate DAF-21 involvement in heat 
        stress response and thermotolerance.
      supported_by:
        - reference_id: PMID:29949773
          supporting_text: We measured mRNA levels of a range of heat-inducible 
            chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90
  - term:
      id: GO:0051082
      label: unfolded protein binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: As a molecular chaperone, DAF-21 binds to unfolded or misfolded 
        client proteins to facilitate their proper folding. This is a core 
        molecular function of HSP90.
      action: MODIFY
      reason: GO:0051082 is proposed for obsoletion. DAF-21/HSP90 is an
        ATP-dependent foldase chaperone. The appropriate replacement term is
        GO:0044183 (protein folding chaperone).
      proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: The ATP-dependent molecular chaperone Hsp90 is 
            required for the activation of a variety of client proteins involved
            in various cellular processes
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Direct immunolocalization studies show DAF-21 protein is 
        localized to the perinuclear region in somatic cells of C. elegans.
      action: ACCEPT
      reason: Direct experimental evidence from PMID:12950278 confirms 
        perinuclear localization in C. elegans, supporting the phylogenetic 
        inference.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Nucleotide binding, specifically ATP binding, is a core function 
        of HSP90 proteins required for chaperone activity. This is a general 
        parent term of ATP binding.
      action: ACCEPT
      reason: Nucleotide (ATP) binding is essential for DAF-21 function. This 
        IEA annotation is consistent with more specific experimental evidence 
        for ATP binding and hydrolysis.
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ATP binding annotation based on InterPro domain analysis. 
        Consistent with experimental evidence and IBA annotation.
      action: ACCEPT
      reason: Duplicate of IBA annotation for ATP binding. Both computational 
        and phylogenetic evidence support the well-established ATP binding 
        function.
  - term:
      id: GO:0006457
      label: protein folding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Protein folding annotation from InterPro HSP90 domain. Consistent
        with IBA annotation and experimental evidence.
      action: ACCEPT
      reason: Duplicate annotation for protein folding, a core HSP90 function 
        supported by multiple evidence types.
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: ATP hydrolysis activity annotation from InterPro HSP90 domain. 
        Consistent with IBA annotation and direct biochemical evidence.
      action: ACCEPT
      reason: Duplicate annotation for ATPase activity, supported by direct 
        biochemical measurements (PMID:21980476, PMID:19559711).
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Perinuclear localization from UniProt subcellular location 
        vocabulary mapping. Consistent with IBA and IDA evidence.
      action: ACCEPT
      reason: Duplicate annotation for perinuclear localization supported by 
        direct immunolocalization evidence (PMID:12950278).
  - term:
      id: GO:0051082
      label: unfolded protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: GO:0051082 is proposed for obsoletion. InterPro domain-based
        annotation consistent with the IBA annotation.
      action: MODIFY
      reason: GO:0051082 is proposed for obsoletion. DAF-21/HSP90 is an
        ATP-dependent foldase chaperone. The appropriate replacement term is
        GO:0044183 (protein folding chaperone). Consistent with MODIFY on
        IBA annotation.
      proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
  - term:
      id: GO:0101031
      label: protein folding chaperone complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: DAF-21 functions in multiple chaperone complexes with 
        co-chaperones as documented in ComplexPortal (CPX-3983, CPX-3984, 
        CPX-4002, CPX-4003, CPX-4004).
      action: ACCEPT
      reason: DAF-21 is part of defined chaperone complexes including 
        Hsp90-CDC37, Hsp90-STI-1, and Hsp90-PPH-5 complexes. This is consistent 
        with its function as a component of the cellular chaperone machinery.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: This increase in absorption reflects the binding of 
            two molecules of PPH-5 to the CeHsp90 dimer
  - term:
      id: GO:0140662
      label: ATP-dependent protein folding chaperone
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: DAF-21 is an ATP-dependent protein folding chaperone. This 
        molecular function term accurately captures the core activity of the 
        protein.
      action: ACCEPT
      reason: This term precisely describes DAF-21 function - it is an 
        ATP-dependent chaperone that promotes protein folding. Well supported by
        experimental evidence.
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: The ATP-dependent molecular chaperone Hsp90 is 
            required for the activation of a variety of client proteins involved
            in various cellular processes
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11809970
    review:
      summary: This annotation captures DAF-21 interaction with UNC-45, an Hsp90
        co-chaperone required for myosin folding. The interaction is 
        functionally relevant for muscle cell maintenance.
      action: MODIFY
      reason: While the interaction with UNC-45 is valid, "protein binding" is 
        too general and uninformative. The annotation would be better 
        represented by a more specific term capturing the co-chaperone 
        interaction.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:11809970
          supporting_text: Role of the myosin assembly protein UNC-45 as a 
            molecular chaperone for myosin.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14992718
    review:
      summary: Interaction with DAF-1 (TGF-beta type I receptor) identified in 
        systematic interactome mapping of TGF-beta signaling network.
      action: MODIFY
      reason: While the protein interaction is valid, "protein binding" is too 
        general. HSP90 chaperoning of receptor kinases is a known function.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:14992718
          supporting_text: Systematic interactome mapping and genetic 
            perturbation analysis of a C.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19467242
    review:
      summary: Interaction with STI-1, the C. elegans Hop/Sti1 ortholog that 
        functions as a co-chaperone linking Hsp70 and Hsp90 systems.
      action: MODIFY
      reason: The interaction with STI-1/Hop is a well-characterized 
        co-chaperone interaction. A more specific term would be more 
        informative.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:19467242
          supporting_text: 2009 May 23. C. elegans STI-1, the homolog of 
            Sti1/Hop, is involved in aging and stress response.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19559711
    review:
      summary: Interaction with STI-1 confirmed biochemically. STI-1 inhibits 
        DAF-21 ATPase activity upon binding.
      action: MODIFY
      reason: Duplicate annotation for STI-1 interaction. "Protein binding" is 
        too vague for this well-characterized co-chaperone interaction.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:19559711
          supporting_text: 2009 Jun 25. The non-canonical Hop protein from 
            Caenorhabditis elegans exerts essential functions and forms binary 
            complexes with either Hsc70 or Hsp90.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23332754
    review:
      summary: Interaction with UNC-45 in the context of myofilament formation 
        in C. elegans.
      action: MODIFY
      reason: Valid co-chaperone interaction. Recommend more specific term.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:23332754
          supporting_text: The myosin chaperone UNC-45 is organized in tandem 
            modules to support myofilament formation in C.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23746847
    review:
      summary: This study established transcellular chaperone signaling where 
        HSP-90 in one tissue can induce proteostasis responses in other tissues.
      action: MODIFY
      reason: '"Protein binding" is too general. This study demonstrates tissue-nonautonomous
        effects but the molecular interactions captured are not well-served by this
        term.'
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:23746847
          supporting_text: Regulation of organismal proteostasis by 
            transcellular chaperone signaling.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:14992718
    review:
      summary: DAF-21 homodimerization is essential for HSP90 function. The 
        protein exists as a homodimer with C-terminal dimerization domain.
      action: ACCEPT
      reason: HSP90 homodimerization is a core structural feature required for 
        chaperone function. This annotation correctly captures DAF-21 
        self-association.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: This increase in absorption reflects the binding of 
            two molecules of PPH-5 to the CeHsp90 dimer
        - reference_id: PMID:14992718
          supporting_text: Systematic interactome mapping and genetic 
            perturbation analysis of a C.
  - term:
      id: GO:0006457
      label: protein folding
    evidence_type: IDA
    original_reference_id: PMID:21980476
    review:
      summary: Direct experimental evidence from RNAi knockdown and mutant 
        analysis showing DAF-21 is required for proper myosin folding in muscle 
        cells. Reduction of DAF-21 leads to myosin aggregation.
      action: ACCEPT
      reason: Strong experimental evidence from direct assays showing DAF-21 is 
        required for protein folding in vivo, particularly for myosin in muscle 
        cells.
      supported_by:
        - reference_id: PMID:21980476
          supporting_text: aggregates of the myosin MYO-3 are visible in muscle 
            cells, if DAF-21 is depleted, implying a role of Hsp90 in the 
            maintenance of muscle cell functionality
  - term:
      id: GO:0072542
      label: protein phosphatase activator activity
    evidence_type: IDA
    original_reference_id: PMID:26593036
    review:
      summary: DAF-21 directly activates the protein phosphatase PPH-5 (PP5 
        ortholog). The interaction promotes PPH-5 phosphatase activity and is 
        required for dephosphorylation of native clients.
      action: ACCEPT
      reason: This is a well-characterized molecular function demonstrated 
        through biochemical assays. DAF-21 activates PPH-5 phosphatase activity 
        through direct interaction.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: we observed an increase of the phosphatase activity 
            in the presence of C. elegans Hsp90 (CeHsp90)
  - term:
      id: GO:0009408
      label: response to heat
    evidence_type: IGI
    original_reference_id: PMID:16916933
    review:
      summary: DAF-21 is part of the HSF-1 pathway required for heat stress 
        response and thermotolerance. The gene is required for immunity response
        to pathogens and heat stress survival.
      action: ACCEPT
      reason: Heat stress response is a well-documented function of HSP90 
        proteins. The IGI evidence with HSF-1 demonstrates DAF-21 functions in 
        the heat shock response pathway.
      supported_by:
        - reference_id: PMID:16916933
          supporting_text: The HSF-1 defense response is independent of the p38 
            MAPK/PMK-1 pathway and requires a system of chaperones including 
            small and 90-kDa inducible HS proteins
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IGI
    original_reference_id: PMID:16916933
    review:
      summary: DAF-21 is required for C. elegans innate immunity against 
        Gram-negative pathogens including Pseudomonas aeruginosa, as part of the
        HSF-1-mediated defense pathway.
      action: KEEP_AS_NON_CORE
      reason: While HSP90 is part of the stress-induced immune response pathway,
        this represents a downstream consequence of chaperone function rather 
        than a core molecular activity. Keep as non-core biological function.
      supported_by:
        - reference_id: PMID:16916933
          supporting_text: HSF-1 is required for C. elegans immunity against 
            Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and 
            Enterococcus faecalis
  - term:
      id: GO:0034605
      label: cellular response to heat
    evidence_type: IMP
    original_reference_id: PMID:29949773
    review:
      summary: DAF-21 is induced by heat stress in a PQM-1-dependent manner and 
        is required for maintaining proteostasis under heat stress conditions.
      action: ACCEPT
      reason: Strong experimental support for DAF-21 role in cellular response 
        to heat through mutant phenotype analysis and expression studies.
      supported_by:
        - reference_id: PMID:29949773
          supporting_text: We measured mRNA levels of a range of heat-inducible 
            chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90
  - term:
      id: GO:0050821
      label: protein stabilization
    evidence_type: IMP
    original_reference_id: PMID:29949773
    review:
      summary: DAF-21 is required for protein stabilization and prevention of 
        misfolding during cellular stress. Transcellular chaperone signaling 
        activates DAF-21 to maintain proteostasis across tissues.
      action: ACCEPT
      reason: Direct experimental evidence from mutant phenotype analysis 
        demonstrating DAF-21 role in preventing protein misfolding.
      supported_by:
        - reference_id: PMID:29949773
          supporting_text: Both TCS pathways can induce hsp-90 in muscle cells 
            and facilitate amelioration of Abeta3-42-associated toxicity
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IPI
    original_reference_id: PMID:26593036
    review:
      summary: DAF-21 forms heterotetrameric complexes with PPH-5, with two 
        PPH-5 molecules binding to the DAF-21 dimer. Complex formation 
        demonstrated by analytical ultracentrifugation.
      action: ACCEPT
      reason: Direct biophysical evidence for complex formation between DAF-21 
        and PPH-5 with defined stoichiometry.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: This increase in absorption reflects the binding of 
            two molecules of PPH-5 to the CeHsp90 dimer
  - term:
      id: GO:1990634
      label: protein phosphatase 5 binding
    evidence_type: IPI
    original_reference_id: PMID:26593036
    review:
      summary: DAF-21 directly binds PPH-5 (protein phosphatase 5 ortholog) 
        through its C-terminal MEEVD motif and additional interaction sites. 
        This binding activates the phosphatase.
      action: ACCEPT
      reason: Highly specific and informative annotation. Direct biochemical and
        biophysical evidence demonstrates this interaction.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: The TPR domain is found in human PP5 and in its 
            homologs from Saccharomyces cerevisiae (PPT1) and Caenorhabditis 
            elegans (PPH-5)
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IDA
    original_reference_id: PMID:26593036
    review:
      summary: Direct evidence for DAF-21 complex formation from analytical 
        ultracentrifugation and SAXS experiments showing defined stoichiometry 
        of Hsp90-PPH-5 complexes.
      action: ACCEPT
      reason: Duplicate annotation for complex membership with direct 
        experimental evidence. Accept both as they represent different evidence 
        types.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: "A global fit confirms the stoichiometry and suggests a
            binding affinity in the range of 1 μM for the first and second PPH-5 molecule"
  - term:
      id: GO:0035259
      label: nuclear glucocorticoid receptor binding
    evidence_type: IPI
    original_reference_id: PMID:26593036
    review:
      summary: DAF-21 was shown to bind the glucocorticoid receptor (GR) ligand 
        binding domain in heterologous assays. Ternary complexes of 
        DAF-21-PPH-5-GR were demonstrated.
      action: KEEP_AS_NON_CORE
      reason: This annotation was derived from experiments using heterologous 
        substrates (human GR) to study DAF-21 mechanism. While it demonstrates 
        conserved HSP90 function, it does not represent a native C. elegans 
        interaction. Keep as non-core since it reflects conserved biochemical 
        properties.
      supported_by:
        - reference_id: PMID:26593036
          supporting_text: ternary complexes with the glucocorticoid receptor 
            (GR) are cooperatively formed by full-length Hsp90 and PPH-5
  - term:
      id: GO:0006611
      label: protein export from nucleus
    evidence_type: IMP
    original_reference_id: PMID:23396260
    review:
      summary: DAF-21 regulates YAP-1 nuclear export after heat shock treatment.
        Knockdown of DAF-21 blocks the nuclear export of YAP-1 during recovery 
        from heat stress.
      action: KEEP_AS_NON_CORE
      reason: This is a specific downstream effect of DAF-21 chaperone activity 
        on YAP-1 subcellular localization, rather than a core molecular 
        function. Keep as non-core biological process.
      supported_by:
        - reference_id: PMID:23396260
          supporting_text: Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block 
            the nuclear export of YAP-1 during this recovery
  - term:
      id: GO:0006935
      label: chemotaxis
    evidence_type: IGI
    original_reference_id: PMID:7828815
    review:
      summary: daf-21 mutants show defects in chemotaxis to non-volatile and 
        volatile attractants. This function is mediated through DAF-21 role in 
        chemosensory signal transduction, likely by stabilizing DAF-11 guanylyl 
        cyclase.
      action: KEEP_AS_NON_CORE
      reason: Chemotaxis defects in daf-21 mutants reflect the requirement for 
        DAF-21 in chemosensory neuron function, likely through client protein 
        stabilization. This is a developmental/behavioral phenotype rather than 
        core molecular function.
      supported_by:
        - reference_id: PMID:7828815
          supporting_text: both mutants are defective in taxis to volatile 
            attractants detected primarily by the amphid neuron AWC
  - term:
      id: GO:0050920
      label: regulation of chemotaxis
    evidence_type: IMP
    original_reference_id: PMID:7828815
    review:
      summary: daf-21 mutants show altered chemosensory behaviors, indicating a 
        role in regulating chemotaxis through sensory signal transduction.
      action: KEEP_AS_NON_CORE
      reason: This represents a phenotypic consequence of DAF-21 function in 
        chemosensory neurons rather than a core molecular function. Keep as 
        non-core.
      supported_by:
        - reference_id: PMID:7828815
          supporting_text: daf-11 and daf-21 mutations were previously shown to 
            cause inappropriate response to the dauer-inducing pheromone
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17610845
    review:
      summary: Interaction with FKB-6, the large TPR-containing immunophilin in 
        C. elegans. FKB-6 binds DAF-21 C-terminal MEEVD peptide via its TPR 
        domain.
      action: MODIFY
      reason: Valid co-chaperone interaction. "Protein binding" is too general.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:17610845
          supporting_text: Cloning, expression and characterisation of FKB-6, 
            the sole large TPR-containing immunophilin from C.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24012004
    review:
      summary: Interaction with EBAX-1, a Cullin-RING E3 ligase component, 
        demonstrating DAF-21 role in protein quality control of the SAX-3/Robo 
        receptor.
      action: MODIFY
      reason: Valid interaction but "protein binding" is too vague. This 
        interaction is in the context of protein quality control.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:24012004
          supporting_text: The EBAX-type Cullin-RING E3 ligase and Hsp90 guard 
            the protein quality of the SAX-3/Robo receptor in developing 
            neurons.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16672054
    review:
      summary: DAF-21 was identified as a LET-756/FGF interactor in a yeast 
        two-hybrid screen. The interaction was validated by 
        co-immunoprecipitation in mammalian cells, though with lower strength 
        than other partners.
      action: MODIFY
      reason: The interaction with LET-756 (FGF) was detected in yeast 
        two-hybrid and confirmed by co-immunoprecipitation. However, "protein 
        binding" is too general for an HSP90 chaperone interaction. The authors 
        note that HSP family members are sometimes considered false positives in
        Y2H screens.
      proposed_replacement_terms:
        - id: GO:0051879
          label: Hsp90 protein binding
      supported_by:
        - reference_id: PMID:16672054
          supporting_text: DAF-21, a chaperone of the HSP-90 family, involved in
            chemosensory transduction and insulin signalization
  - term:
      id: GO:0051604
      label: protein maturation
    evidence_type: NAS
    original_reference_id: PMID:20880838
    review:
      summary: This annotation from ComplexPortal reflects DAF-21/HSP90 role in 
        client protein maturation. The study characterized C. elegans 
        Cdc37-Hsp90 complexes and their role in kinase client maturation.
      action: ACCEPT
      reason: Protein maturation is a well-documented function of HSP90 
        chaperones, particularly in the context of kinase client activation. The
        NAS evidence is supported by direct biochemical studies of the C. 
        elegans HSP90-CDC-37 complex.
      supported_by:
        - reference_id: PMID:20880838
          supporting_text: Hsp90 is an ATP-dependent molecular chaperone, which 
            facilitates the activation and stabilization of hundreds of client 
            proteins in cooperation with a defined set of cofactors
  - term:
      id: GO:0045121
      label: membrane raft
    evidence_type: HDA
    original_reference_id: PMID:21070894
    review:
      summary: DAF-21 was identified in a proteomic analysis of C. elegans lipid
        raft fractions, suggesting some membrane raft association.
      action: KEEP_AS_NON_CORE
      reason: Mass spectrometry identification in membrane raft fractions 
        suggests some membrane association, but this is not the primary 
        localization. Keep as non-core localization.
      supported_by:
        - reference_id: PMID:21070894
          supporting_text: 2010 Nov 8. An analysis of the Caenorhabditis elegans
            lipid raft proteome using geLC-MS/MS.
  - term:
      id: GO:0016887
      label: ATP hydrolysis activity
    evidence_type: IDA
    original_reference_id: PMID:19559711
    review:
      summary: Direct biochemical measurement of DAF-21 ATPase activity and its 
        regulation by co-chaperone STI-1 (Hop).
      action: ACCEPT
      reason: Direct enzymatic assay demonstrating DAF-21 ATPase activity. This 
        is a core molecular function of HSP90 proteins.
      supported_by:
        - reference_id: PMID:19559711
          supporting_text: 2009 Jun 25. The non-canonical Hop protein from 
            Caenorhabditis elegans exerts essential functions and forms binary 
            complexes with either Hsc70 or Hsp90.
  - term:
      id: GO:0002119
      label: nematode larval development
    evidence_type: IMP
    original_reference_id: PMID:10790386
    review:
      summary: daf-21 null mutants show early larval lethality, and hypomorphic 
        mutants (E292K) have developmental defects. The gene is essential for 
        larval development.
      action: ACCEPT
      reason: daf-21 is essential for C. elegans development. Null mutants are 
        lethal and hypomorphic mutants show developmental abnormalities.
      supported_by:
        - reference_id: PMID:10790386
          supporting_text: daf-21 encodes the heat-shock protein 90 (Hsp90)
  - term:
      id: GO:0008340
      label: determination of adult lifespan
    evidence_type: IGI
    original_reference_id: PMID:14668486
    review:
      summary: DAF-21 functions in the insulin-like signaling pathway to 
        regulate longevity. Downregulation of chaperones including DAF-21 
        decreases longevity of long-lived mutant animals.
      action: KEEP_AS_NON_CORE
      reason: While DAF-21 contributes to lifespan regulation, this represents a
        downstream phenotypic consequence of chaperone function affecting 
        proteostasis. Keep as non-core biological process.
      supported_by:
        - reference_id: PMID:14668486
          supporting_text: Down-regulation of individual molecular chaperones, 
            transcriptional targets of HSF-1, also decreased longevity of 
            long-lived mutant but not wild-type animals
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12950278
    review:
      summary: Direct immunolocalization of DAF-21 shows cytoplasmic 
        distribution in C. elegans tissues, with enrichment in the perinuclear 
        region.
      action: ACCEPT
      reason: Experimental evidence from immunofluorescence studies confirms 
        cytoplasmic localization of DAF-21.
      supported_by:
        - reference_id: PMID:12950278
          supporting_text: 'Caenorhabditis elegans DAF-21 (HSP90) is characteristically
            and predominantly expressed in germline cells: spatial and temporal analysis.'
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12950278
    review:
      summary: Direct immunolocalization showing DAF-21 enrichment in the 
        perinuclear region of somatic cells.
      action: ACCEPT
      reason: Direct experimental evidence for perinuclear localization.
      supported_by:
        - reference_id: PMID:12950278
          supporting_text: 'Caenorhabditis elegans DAF-21 (HSP90) is characteristically
            and predominantly expressed in germline cells: spatial and temporal analysis.'
  - term:
      id: GO:0040024
      label: dauer larval development
    evidence_type: IMP
    original_reference_id: PMID:11677050
    review:
      summary: DAF-21 is required for proper dauer formation, the core phenotype
        that gave the gene its name. daf-21 mutants show dauer formation defects
        and act upstream of DAF-7/TGF-beta in the dauer pathway.
      action: ACCEPT
      reason: Dauer formation is the defining phenotype for which daf-21 was 
        named. This is a well-documented developmental role mediated through 
        DAF-21 chaperone function on signal transduction components.
      supported_by:
        - reference_id: PMID:11677050
          supporting_text: daf-11 gene and a related gene daf-21 act upstream of
            daf-7
  - term:
      id: GO:0040024
      label: dauer larval development
    evidence_type: IGI
    original_reference_id: PMID:11677050
    review:
      summary: Genetic interaction between daf-21 and daf-11 in the dauer 
        formation pathway. Both genes regulate DAF-7 expression and dauer 
        development.
      action: ACCEPT
      reason: Genetic interaction evidence supporting DAF-21 role in dauer 
        formation pathway.
      supported_by:
        - reference_id: PMID:11677050
          supporting_text: daf-11 gene and a related gene daf-21 act upstream of
            daf-7
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:7828815
    title: Multiple chemosensory defects in daf-11 and daf-21 mutants of 
      Caenorhabditis elegans.
    findings:
      - statement: daf-21 mutants are defective in chemotaxis to non-volatile 
          and volatile attractants
        supporting_text: both mutants are defective in taxis to volatile 
          attractants detected primarily by the amphid neuron AWC
      - statement: DAF-21 may mediate sensory transduction for specific 
          chemosensory pathways
        supporting_text: daf-11 and daf-21 mutations were previously shown to 
          cause inappropriate response to the dauer-inducing pheromone
  - id: PMID:10790386
    title: A transmembrane guanylyl cyclase (DAF-11) and Hsp90 (DAF-21) regulate
      a common set of chemosensory behaviors in caenorhabditis elegans.
    findings:
      - statement: daf-21 encodes the C. elegans HSP90 ortholog
        supporting_text: daf-21 encodes the heat-shock protein 90 (Hsp90)
  - id: PMID:11677050
    title: DAF-7/TGF-beta expression required for the normal larval development 
      in C. elegans is controlled by a presumed guanylyl cyclase DAF-11.
    findings:
      - statement: daf-11 and daf-21 act upstream of daf-7 in dauer pathway
        supporting_text: daf-11 gene and a related gene daf-21 act upstream of 
          daf-7
  - id: PMID:11809970
    title: Role of the myosin assembly protein UNC-45 as a molecular chaperone 
      for myosin.
    findings:
      - statement: UNC-45 TPR domain binds HSP90
        supporting_text: The amino-terminal tetratricopeptide repeat domain of 
          UNC-45 bound the molecular chaperone Hsp90
  - id: PMID:12950278
    title: 'Caenorhabditis elegans DAF-21 (HSP90) is characteristically and predominantly
      expressed in germline cells: spatial and temporal analysis.'
    findings:
      - statement: DAF-21 is localized to perinuclear region of somatic cells
        supporting_text: the DAF-21 protein seemed to be localized in the 
          perinuclear region of somatic cells
  - id: PMID:14668486
    title: Regulation of longevity in Caenorhabditis elegans by heat shock 
      factor and molecular chaperones.
    findings:
      - statement: HSF-1 and molecular chaperones regulate longevity
        supporting_text: Down-regulation of individual molecular chaperones, 
          transcriptional targets of HSF-1, also decreased longevity of 
          long-lived mutant but not wild-type animals
  - id: PMID:14992718
    title: Systematic interactome mapping and genetic perturbation analysis of a
      C. elegans TGF-beta signaling network.
    findings:
      - statement: DAF-21 interacts with DAF-1 TGF-beta receptor
        supporting_text: Yeast two-hybrid (Y2H) screens starting with known 
          DAF-7/TGF-beta pathway components defined a network of 71 interactions
          among 59 proteins
  - id: PMID:16916933
    title: Heat-shock transcription factor (HSF)-1 pathway required for 
      Caenorhabditis elegans immunity.
    findings:
      - statement: HSF-1 pathway requires 90-kDa inducible heat shock proteins 
          for immunity
        supporting_text: The HSF-1 defense response is independent of the p38 
          MAPK/PMK-1 pathway and requires a system of chaperones including small
          and 90-kDa inducible HS proteins
  - id: PMID:17610845
    title: Cloning, expression and characterisation of FKB-6, the sole large 
      TPR-containing immunophilin from C. elegans.
    findings:
      - statement: FKB-6 TPR domain interacts with DAF-21 C-terminal MEEVD 
          peptide
        supporting_text: NMR studies of the interaction between FKB-6 and the 
          C-terminal DAF-21 pentapeptide MEEVD
  - id: PMID:19467242
    title: C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and 
      stress response.
    findings:
      - statement: STI-1 binds both Hsp70 and DAF-21/Hsp90
        supporting_text: CeSTI-1 can bind with both Hsp70 and Hsp90 homologs
  - id: PMID:19559711
    title: The non-canonical Hop protein from Caenorhabditis elegans exerts 
      essential functions and forms binary complexes with either Hsc70 or Hsp90.
    findings:
      - statement: C. elegans Hop/STI-1 forms binary complexes with DAF-21
        supporting_text: forms binary complexes with either Hsc70 or Hsp90
      - statement: DAF-21 ATPase activity is inhibited by Hop binding
        supporting_text: inhibition of the Hsp90 ATPase activity can be observed
          upon binding of CeHop
  - id: PMID:21070894
    title: An analysis of the Caenorhabditis elegans lipid raft proteome using 
      geLC-MS/MS.
    findings:
      - statement: DAF-21 identified in lipid raft proteome
        supporting_text: A study of the lipid raft proteome of C. elegans is 
          presented here
  - id: PMID:21980476
    title: Downregulation of the Hsp90 system causes defects in muscle cells of 
      Caenorhabditis elegans.
    findings:
      - statement: DAF-21 is required for proper myosin localization in muscle
        supporting_text: aggregates of the myosin MYO-3 are visible in muscle 
          cells, if DAF-21 is depleted, implying a role of Hsp90 in the 
          maintenance of muscle cell functionality
      - statement: daf-21(p673) E292K mutant has reduced ATPase activity
        supporting_text: "At 30°C, the ATPase activity of E292K-DAF-21 was found to
          be 0.1 min−1, while that of wt-DAF-21 was 0.6 min−1 (Figure 1B)"
  - id: PMID:23332754
    title: The myosin chaperone UNC-45 is organized in tandem modules to support
      myofilament formation in C. elegans.
    findings:
      - statement: UNC-45 interacts with DAF-21 during myofilament formation
        supporting_text: For Hsp90 (DAF-21 in C. elegans)
  - id: PMID:23396260
    title: Yes-associated protein homolog, YAP-1, is involved in the 
      thermotolerance and aging in the nematode Caenorhabditis elegans.
    findings:
      - statement: DAF-21 regulates YAP-1 nuclear export after heat shock
        supporting_text: Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block 
          the nuclear export of YAP-1 during this recovery
  - id: PMID:23746847
    title: Regulation of organismal proteostasis by transcellular chaperone 
      signaling.
    findings:
      - statement: HSP-90 expression in one tissue induces systemic stress 
          response
        supporting_text: elevated expression of HSP90 in intestine or neuronal 
          cells
  - id: PMID:24012004
    title: The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein 
      quality of the SAX-3/Robo receptor in developing neurons.
    findings:
      - statement: DAF-21 interacts with EBAX-1 for protein quality control
        supporting_text: EBAX-1 also binds to DAF-21, a cytosolic Hsp90 
          chaperone
  - id: PMID:26593036
    title: The activity of protein phosphatase 5 towards native clients is 
      modulated by the middle- and C-terminal domains of Hsp90.
    findings:
      - statement: DAF-21 binds and activates PPH-5 phosphatase
        supporting_text: we observed an increase of the phosphatase activity in 
          the presence of C. elegans Hsp90 (CeHsp90)
      - statement: Two PPH-5 molecules bind per DAF-21 dimer
        supporting_text: This increase in absorption reflects the binding of two
          molecules of PPH-5 to the CeHsp90 dimer
      - statement: Ternary complexes form with glucocorticoid receptor as client
        supporting_text: ternary complexes with the glucocorticoid receptor (GR)
          are cooperatively formed by full-length Hsp90 and PPH-5
  - id: PMID:29949773
    title: A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling 
      and Regulates Organismal Proteostasis.
    findings:
      - statement: DAF-21 is induced by heat stress in pqm-1-dependent manner
        supporting_text: We measured mRNA levels of a range of heat-inducible 
          chaperones, including stress-inducible hsp-70 (C12C8.1), hsp-90
      - statement: DAF-21 prevents protein misfolding and maintains proteostasis
        supporting_text: Both TCS pathways can induce hsp-90 in muscle cells and
          facilitate amelioration of Abeta3-42-associated toxicity
  - id: PMID:16672054
    title: Direct and heterologous approaches to identify the LET-756/FGF 
      interactome.
    findings:
      - statement: DAF-21 interacts with LET-756/FGF in yeast two-hybrid screen
        supporting_text: DAF-21, a chaperone of the HSP-90 family
  - id: PMID:20880838
    title: Cdc37-Hsp90 complexes are responsive to nucleotide-induced 
      conformational changes and binding of further cofactors.
    findings:
      - statement: C. elegans Hsp90 forms complexes with Cdc37 for kinase client
          processing
        supporting_text: Hsp90 is an ATP-dependent molecular chaperone, which 
          facilitates the activation and stabilization of hundreds of client 
          proteins
  - id: file:worm/daf-21/daf-21-deep-research-falcon.md
    title: Deep research report on daf-21
    findings: []
core_functions:
  - description: DAF-21 is the sole C. elegans HSP90, an ATP-dependent molecular
      chaperone that promotes protein folding and stabilization of client 
      proteins. Demonstrated through biochemical assays (ATPase activity, client
      binding) and genetic analysis (aggregation of myosin in knockdowns).
    molecular_function:
      id: GO:0140662
      label: ATP-dependent protein folding chaperone
  - description: DAF-21 directly activates PPH-5 phosphatase activity through 
      binding to its TPR domain and additional interaction sites. Demonstrated 
      through biochemical assays (PMID:26593036).
    molecular_function:
      id: GO:0072542
      label: protein phosphatase activator activity
  - description: Core HSP90 molecular function as chaperone. DAF-21 binds 
      unfolded or misfolded client proteins to facilitate their proper folding 
      or targeting for degradation.
    molecular_function:
      id: GO:0044183
      label: protein folding chaperone
proposed_new_terms: []
suggested_questions:
  - question: What are the key client proteins for DAF-21 in dauer formation 
      signaling, beyond DAF-11?
  - question: Does DAF-21 have distinct functions in germline versus somatic 
      tissues given its differential expression?
suggested_experiments:
  - description: Identify native DAF-21 client proteins by AP-MS. While some 
      clients are known (DAF-11, WEE-1.3), a systematic identification of native
      DAF-21 clients in C. elegans would clarify its cellular roles.
    hypothesis: DAF-21 interacts with multiple signal transduction proteins 
      beyond DAF-11
  - description: Determine tissue-specific requirements for DAF-21 using 
      tissue-specific RNAi. Understanding which tissues require DAF-21 for 
      viability and specific phenotypes would clarify its developmental roles.
    hypothesis: DAF-21 is required in multiple tissues for different aspects of 
      development
tags:
  - caeel-proteostasis

daf-21

Gene Description

Existing Annotations Review

Core Functions

DAF-21 is the sole C. elegans HSP90, an ATP-dependent molecular chaperone that promotes protein folding and stabilization of client proteins. Demonstrated through biochemical assays (ATPase activity, client binding) and genetic analysis (aggregation of myosin in knockdowns).

DAF-21 directly activates PPH-5 phosphatase activity through binding to its TPR domain and additional interaction sites. Demonstrated through biochemical assays (PMID:26593036).

Core HSP90 molecular function as chaperone. DAF-21 binds unfolded or misfolded client proteins to facilitate their proper folding or targeting for degradation.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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