Activator of 90 kDa heat shock protein ATPase homolog 1 (AHA1/AHSA1) is the most potent known stimulator of HSP90 ATP hydrolysis, functioning as an HSP90 co-chaperone that accelerates the HSP90 conformational/ATPase cycle. AHSA1 is a two-domain protein (N-terminal and C-terminal) connected by a flexible linker; the N-terminal domain binds the HSP90 middle domain via conserved NxNNWHW and RKxK motifs (required for maximal ATPase stimulation and catalytic-loop positioning), while the C-terminal domain stabilizes the dimerized HSP90 N-terminal domains (DOI:10.1038/s44319-024-00193-8). AHSA1 is ~30-fold less abundant than HSP90 and can act asymmetrically, with a single AHSA1 molecule sufficient to stimulate HSP90 ATPase activity. One or two AHSA1 molecules can bind per HSP90 dimer, with stoichiometry differentially regulating HSP90 properties (DOI:10.1016/j.bpj.2023.07.020). AHSA1 competes with inhibitory co-chaperones FNIP1 and TSC1 for HSP90 binding, providing reciprocal regulation of client protein chaperoning. A metazoan-specific N-terminal intrinsic chaperone domain (ICD, aa ~1-20) both confers HSP90-independent holdase activity (preventing aggregation of model substrates) and dampens ATPase stimulation by interfering with NxNNWHW function, also controlling regulated recruitment to HSP90 in cells (DOI:10.1038/s44319-024-00193-8). AHSA1 modulates maturation of HSP90 clients including kinases, steroid receptors, and Dicer1 (affecting microRNA biogenesis) (DOI:10.1093/nar/gkac528). AHSA1 is being explored as a therapeutic target in multiple myeloma (bufalin/KU-177 binding at K137), cystic fibrosis (CFTR proteostasis), and neurodegeneration (tauopathies) (DOI:10.1186/s13046-021-02220-1, DOI:10.3389/fnmol.2024.1509280).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001671 ATPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for ATPase activator activity based on phylogenetic inference (PANTHER). This is the core molecular function of AHSA1. Aha1 was identified as the activator of Hsp90 ATPase in yeast and human, stimulating ATPase activity 5-fold in vitro (PMID:12604615) and confirmed across multiple studies (PMID:12504007, PMID:29127155, PMID:27353360). The IBA annotation is well supported by conserved function across yeast (S. cerevisiae Aha1, Hch1) and S. pombe orthologs included in the PANTHER family. Reason: ATPase activator activity is the primary, evolutionarily conserved molecular function of AHSA1. Multiple independent experimental studies confirm this function (PMID:12504007, PMID:12604615, PMID:27353360, PMID:29127155), and the IBA phylogenetic inference is sound, supported by orthologs in yeast. Supporting Evidence: PMID:12504007 A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. PMID:12604615 Aha1 but not Hch1 stimulated the intrinsic ATPase activity of Hsp90 5-fold file:human/AHSA1/AHSA1-deep-research-falcon.md AHSA1 is the HSP90 co-chaperone that potently stimulates HSP90 ATPase activity by promoting the closed, N-terminally dimerized state and engaging catalytic elements of HSP90. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytosol localization based on phylogenetic inference. AHSA1 is predominantly cytosolic, consistent with its role as an HSP90 co-chaperone. UniProt records cytoplasm/cytosol as the primary subcellular location (PMID:11554768), and HPA immunofluorescence data supports cytosol localization (GO_REF:0000052). Reason: Cytosol is the well-established primary localization of AHSA1, consistent with its function as an HSP90 co-chaperone in the cytoplasm. Supported by IDA from HPA and UniProt subcellular location annotation. |
| GO:0006457 protein folding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for protein folding based on phylogenetic inference. AHSA1 participates in protein folding indirectly by stimulating the HSP90 ATPase cycle, which is required for HSP90-dependent client protein maturation. Yeast Aha1 deletion impairs activation of the Hsp90 client v-Src (PMID:12504007, PMID:12604615), and human AHSA1 competes with inhibitory co-chaperones to regulate HSP90 client chaperoning (PMID:27353360, PMID:29127155). The term is at an appropriate level of generality for the biological process. Reason: Protein folding is an appropriate biological process for AHSA1, which participates in HSP90-mediated client protein folding/maturation by stimulating the HSP90 chaperone cycle. The IBA inference is supported by experimental evidence in yeast and human showing that Aha1 is required for efficient activation of Hsp90 clients. Supporting Evidence: PMID:12604615 Aha1 and Hch1 contributed to efficient activation of the heterologous Hsp90 client protein v-Src PMID:29127155 Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity ... prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90 |
| GO:0001671 ATPase activator activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for ATPase activator activity inferred from InterPro domain IPR015310 (AHSA1-like_N). This is consistent with the core function of AHSA1 and is well supported by experimental evidence across multiple publications. Reason: The InterPro-to-GO mapping is correct. The AHSA1 N-terminal domain (Aha1_N, Pfam PF09229) is the domain responsible for binding the HSP90 middle domain and stimulating ATPase activity (PMID:12604615). This IEA annotation is redundant with the IBA and IDA annotations but correctly captures the function. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation for ER localization mapped from UniProt subcellular location. UniProt notes that AHSA1 "may transiently interact with the endoplasmic reticulum" based on PMID:11554768 (Sevier and Machamer 2001), which identified AHSA1 (then called p38) as interacting with VSV G glycoprotein. The ER localization is likely a minor or transient association rather than a primary localization. Reason: The ER association is based on early work showing AHSA1 interacts with VSV G glycoprotein and may transiently associate with the ER (PMID:11554768). This is not a core localization for AHSA1, whose primary function occurs in the cytosol. The UniProt annotation itself qualifies this as transient. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for cytosol localization mapped from UniProt subcellular location vocabulary. Consistent with the primary localization of AHSA1 and supported by IDA (HPA) and IBA evidence. Reason: Cytosol is the well-established primary localization of AHSA1. This IEA annotation is consistent with the IDA and IBA annotations for the same term and is correctly mapped from UniProt subcellular location. |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for protein-folding chaperone binding inferred from InterPro domain IPR015310. AHSA1 directly binds HSP90, which is a protein-folding chaperone, so this annotation is accurate. The binding is well characterized: the N-terminal domain of AHSA1 binds the middle domain of HSP90 (PMID:12604615), and the C-terminal domain stabilizes the dimerized N-terminal domains of HSP90 (PMID:33808352). Reason: AHSA1 is a well-established HSP90-binding co-chaperone. The InterPro-to-GO mapping correctly captures the chaperone binding function. This is supported by multiple experimental studies (PMID:12504007, PMID:12604615, PMID:27353360, PMID:29127155). |
| GO:0005515 protein binding | IPI PMID:12604615 Aha1 binds to the middle domain of Hsp90, contributes to cli... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Lotz et al. 2003, which demonstrated that Aha1 binds to the middle domain of Hsp90 using biochemical approaches including co-immunoprecipitation and direct binding assays. The WITH column indicates interaction with HSP90AA1 (P07900). While the interaction is real and well-characterized, "protein binding" is uninformative since the specific interaction is better captured by GO:0051879 (Hsp90 protein binding). Reason: The underlying interaction with HSP90 is the core function of AHSA1 and is well-documented (PMID:12604615). However, GO:0005515 (protein binding) is too vague. The interaction is more precisely captured by GO:0051879 (Hsp90 protein binding), which is already annotated from other evidence. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:12604615 We have identified Aha1 (activator of Hsp90 ATPase) and its relative Hch1 (high copy Hsp90 suppressor) as binding partners of Hsp90 in Saccharomyces cerevisiae. By using genetic and biochemical approaches, the middle domain of Hsp90 (amino acids 272-617) was found to mediate the interaction with Aha1 and Hch1. |
| GO:0005515 protein binding | IPI PMID:16696853 A yeast 2-hybrid analysis of human GTP cyclohydrolase I prot... | KEEP AS NON CORE | Summary: IPI protein binding annotation from IntAct, based on Swick and Kapatos 2006, which identified AHSA1 as interacting with GCH1 (GTP cyclohydrolase I, P30793) using yeast two-hybrid screen and validated by GST pull-down assay. The authors note that "the physiological relevance of the Aha1-GCH1 interaction requires further study" and speculate it may recruit GCH1 into the eNOS/Hsp90 complex. This is a secondary, possibly indirect interaction. Reason: The interaction with GCH1 was detected by yeast two-hybrid and validated by GST pull-down (PMID:16696853), but its physiological relevance is uncertain. The authors themselves state the relevance "requires further study." This may reflect indirect bridging through HSP90 rather than a direct functional interaction. Keeping as non-core since the interaction was validated but may not represent a core AHSA1 function. Supporting Evidence: PMID:16696853 The interaction of one of these clones, Activator of Heat Shock 90 kDa Protein (Aha1), with GCH1 was validated by glutathione-s-transferase (GST) pull-down assay. Although the physiological relevance of the Aha1-GCH1 interaction requires further study |
| GO:0005515 protein binding | IPI PMID:19875381 A proteomic investigation of ligand-dependent HSP90 complexe... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Gano and Simon 2010, which identified AHSA1 as a component of HSP90 complexes by tandem affinity purification and LC-MS/MS. The WITH column indicates interaction with HSP90AA1 (P07900). This is a high-throughput proteomics study that characterized the nucleotide-dependent HSP90 interactome. The AHSA1-HSP90 interaction is well established. Reason: The interaction with HSP90 is the core function of AHSA1. GO:0005515 (protein binding) is uninformative; the specific interaction is better captured by GO:0051879 (Hsp90 protein binding). Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:19875381 We identified 52 known and novel components of HSP90 complexes that are regulated by these ligands, including several co-chaperones. |
| GO:0005515 protein binding | IPI PMID:20618441 CHIP participates in protein triage decisions by preferentia... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Stankiewicz et al. 2010. The WITH column indicates interaction with HSP90AB1 (P08238). This study investigated CHIP-mediated ubiquitination and tested the influence of Aha1 on HSP90 ATPase activity in the context of CHIP. AHSA1 is mentioned as an HSP90 co-chaperone tested for its effect on CHIP function. The interaction with HSP90 is incidental to the main focus of the paper. Reason: The interaction detected is between AHSA1 and HSP90AB1, which is the core binding partner. GO:0005515 is too vague; GO:0051879 (Hsp90 protein binding) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:20618441 CHIP did not influence the ATPase cycle of Hsp90 in the absence of co-chaperones or in the presence of the Hsp90 cochaperones Aha1 or p23. |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Taipale et al. 2014, a large-scale quantitative chaperone interaction network study. The WITH column indicates interaction with HSP90AB1 (P08238). This is a systematic proteomics study mapping chaperone-client interactions. AHSA1 was identified as part of the HSP90 interaction network. Reason: The interaction detected is with HSP90AB1. GO:0005515 is too vague for AHSA1, whose binding to HSP90 is its core function. GO:0051879 (Hsp90 protein binding) is the appropriate specific term. Proposed replacements: Hsp90 protein binding |
| GO:0005515 protein binding | IPI PMID:30382094 Structure and pro-toxic mechanism of the human Hsp90/PPIase/... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Oroz et al. 2018, which determined the solution structure of the human Hsp90/FKBP51/Tau complex. The WITH column indicates interaction with HSP90AB1 (P08238). AHSA1 is mentioned as restoring HSP90 ATPase activity that was decreased by FKBP51 binding. This is a functional assay demonstrating AHSA1's role as an HSP90 ATPase activator. Reason: The interaction is with HSP90AB1 and reflects AHSA1's core function as an HSP90 co-chaperone. GO:0005515 is uninformative; GO:0051879 (Hsp90 protein binding) properly captures this interaction. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:30382094 Hsp90 ATPase activity was restored by the addition of Aha1, a strong enhancer of Hsp90 ATPase activity through compaction of the Hsp90 conformation |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: IPI protein binding annotation from IntAct, based on Cho et al. 2022 (OpenCell project), which used endogenous tagging and mass spectrometry to map protein-protein interactions across the human proteome. The WITH column indicates interactions with HSP90AA1 (P07900) and HSP90AB1 (P08238). This is a large-scale systematic study confirming the known AHSA1-HSP90 interaction. Reason: The interactions detected are with both HSP90 isoforms (HSP90AA1 and HSP90AB1), consistent with AHSA1's core function. GO:0005515 is too vague; GO:0051879 (Hsp90 protein binding) properly captures this. Proposed replacements: Hsp90 protein binding |
| GO:0051879 Hsp90 protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for Hsp90 protein binding from combined automated methods (ARBA, mouse ortholog, Ensembl). This is well-supported by extensive experimental evidence: AHSA1 directly binds HSP90AA1 and HSP90AB1 (PMID:12504007, PMID:12604615, PMID:25486457, PMID:27353360, PMID:29127155). HSP90 binding is the core molecular interaction of AHSA1. Reason: Hsp90 protein binding is the core molecular interaction of AHSA1. The automated annotation is correct and supported by multiple independent experimental studies. AHSA1 binds both HSP90 isoforms through its N-terminal and C-terminal domains. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation for cytosol localization from Human Protein Atlas (HPA) based on curation of immunofluorescence data. This is consistent with AHSA1's role as a cytosolic HSP90 co-chaperone and is supported by UniProt subcellular location annotation (PMID:11554768). Reason: Cytosol is the primary localization of AHSA1, directly demonstrated by immunofluorescence (HPA) and consistent with its function as an HSP90 co-chaperone in the cytoplasm. |
| GO:0036506 maintenance of unfolded protein | EXP PMID:37486705 Human Aha1's N-terminal extension confers it holdase activit... | MARK AS OVER ANNOTATED | Summary: EXP annotation for maintenance of unfolded protein from DisProt, based on Tang et al. 2023, which demonstrated that the N-terminal extension (M1-R16) of human Aha1 confers holdase activity in vitro. The holdase activity prevents aggregation of heat-denatured MBP but is abolished by high NaCl concentration. This activity is mediated by the N-terminal extension unique to higher eukaryote Aha1 proteins and is absent from the conserved core domains. Reason: The holdase activity demonstrated in vitro maps to the N-terminal extension (M1-R16) unique to higher eukaryotes, not the conserved Aha1 core domains. The activity is abolished by high NaCl concentration, suggesting electrostatic-driven non-specific interactions (PMID:37486705). No in vivo evidence supports this as a physiological function. AHSA1's core function is HSP90 ATPase activation, not autonomous chaperone activity. Supporting Evidence: PMID:37486705 the highly conserved N-terminal extension spanning M1 to R16 in Aha1 from higher eukaryotes is responsible for the holdase activity of the protein PMID:37486705 since the high concentration of NaCl could abolish the holdase activity of Aha1, the electrostatic interactions mediated by those charged residues in Aha1's N-terminal extension are thus indicated to play a crucial role in the substrate recognition |
| GO:0036506 maintenance of unfolded protein | IDA PMID:37486705 Human Aha1's N-terminal extension confers it holdase activit... | MARK AS OVER ANNOTATED | Summary: IDA annotation for maintenance of unfolded protein from DisProt, based on the same study as above (Tang et al. 2023). This is a duplicate annotation with different evidence code (IDA vs EXP) from the same reference, and the same concerns apply. Reason: Same rationale as the EXP annotation from the same reference. The holdase activity is an in vitro observation dependent on the non-conserved N-terminal extension (M1-R16) and abolished by high salt, suggesting non-specific electrostatic interactions. Not established as a physiological function of AHSA1. Supporting Evidence: PMID:37486705 the highly conserved N-terminal extension spanning M1 to R16 in Aha1 from higher eukaryotes is responsible for the holdase activity of the protein |
| GO:0044183 protein folding chaperone | EXP PMID:33808352 Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Li... | MARK AS OVER ANNOTATED | Summary: EXP annotation for protein folding chaperone from DisProt, based on Hu et al. 2021, which demonstrated using NMR HSQC titrations and ThT assays that full-length human Aha1 interacts with alpha-synuclein and inhibits its aggregation in vitro. The chaperone-like activity requires the N-terminal extension (M1-W27) and/or C-terminal RLF motif, which are peripheral to the conserved core domains (PMID:33808352). The core construct Aha128-335 showed no significant interaction with alpha-synuclein. Reason: The protein folding chaperone annotation for AHSA1 represents an over-annotation. The chaperone-like activity is an in vitro observation dependent on peripheral regions (N-terminal extension and C-terminal RLF motif) not present in the conserved Aha1 core. The core construct Aha128-335 showed no significant interaction with alpha-synuclein (PMID:33808352). No in vivo evidence supports autonomous chaperone function. AHSA1's established role is as an HSP90 ATPase activator co-chaperone, not as an independent protein folding chaperone. Supporting Evidence: PMID:33808352 Without the presence of M1-W27 fragment and RLF (R336L337F338) motif, no significant chemical shift perturbations were observed for the NMR resonances of the residues in Aha128-335 upon the addition of alpha-synuclein PMID:33808352 extensive in vivo studies need to be conducted to precisely decipher the functional roles of Aha1 under different physiological and pathological conditions |
| GO:0044183 protein folding chaperone | IDA PMID:33808352 Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Li... | MARK AS OVER ANNOTATED | Summary: IDA annotation for protein folding chaperone from DisProt, based on the same study (Hu et al. 2021). This is a duplicate annotation with different evidence code (IDA vs EXP) from the same reference, and the same concerns apply. Reason: Same rationale as the EXP annotation from the same reference. The chaperone-like activity depends on peripheral regions absent from the conserved Aha1 core, has no in vivo validation, and does not represent a core function of AHSA1. Supporting Evidence: PMID:33808352 Without the presence of M1-W27 fragment and RLF (R336L337F338) motif, no significant chemical shift perturbations were observed for the NMR resonances of the residues in Aha128-335 upon the addition of alpha-synuclein |
| GO:0051082 unfolded protein binding | EXP PMID:33808352 Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Li... | MARK AS OVER ANNOTATED | Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). The annotation from DisProt is based on PMID:33808352 (Hu et al. 2021), which used NMR HSQC titrations and ThT assays to show that full-length human Aha1 interacts with intrinsically disordered alpha-synuclein and inhibits its aggregation in vitro. However, the core construct Aha128-335 (lacking the N-terminal M1-W27 extension and C-terminal RLF motif) showed no significant interaction with alpha-synuclein, indicating this is not a property of the conserved Aha1 core domains. The authors themselves describe this as "chaperone-like activity" and note that in vivo significance remains unestablished. AHSA1's primary, evolutionarily conserved function is as an HSP90 ATPase activator, not as an independent chaperone. The unfolded protein binding annotation is an over-annotation that conflates an in vitro observation with a core molecular function. Furthermore, GO:0051082 is now formally obsolete. The holdase/chaperone-like activity demonstrated in vitro is better captured by the existing GO:0044183 (protein folding chaperone) and GO:0036506 (maintenance of unfolded protein) annotations already present on this gene. Reason: AHSA1 is primarily an HSP90 co-chaperone whose core function is stimulating HSP90 ATPase activity (PMID:12504007, PMID:29127155). The unfolded protein binding annotation is based on in vitro NMR titration experiments showing that full-length Aha1 interacts with alpha-synuclein (PMID:33808352), but this interaction depends on the N-terminal extension (M1-W27) and C-terminal RLF motif, which are peripheral to the conserved Aha1 domains and absent in lower eukaryotes. The authors state that "extensive in vivo studies need to be conducted to precisely decipher the functional roles of Aha1 under different physiological and pathological conditions" (PMID:33808352). A follow-up study (PMID:37486705) confirmed the holdase activity maps to the N-terminal extension (M1-R16) and is driven by electrostatic interactions that can be abolished by high NaCl concentration, suggesting non-specific binding. Additionally, GO:0051082 is now formally obsolete. The chaperone-like activity is already captured by GO:0044183 and GO:0036506 annotations on this gene from the same research group. Supporting Evidence: PMID:33808352 Without the presence of M1-W27 fragment and RLF (R336L337F338) motif, no significant chemical shift perturbations were observed for the NMR resonances of the residues in Aha128β335 upon the addition of Ξ±-synuclein PMID:33808352 In particular, since Aha1 has been reported to drive the production of pathological tau aggregates by acting as Hsp90's co-chaperone [59], which is in opposite to the inhibition effect of Aha1 on Ξ±-synuclein's aggregation observed by us, extensive in vivo studies need to be conducted to precisely decipher the functional roles of Aha1 under different physiological and pathological conditions. PMID:37486705 the highly conserved N-terminal extension spanning M1 to R16 in Aha1 from higher eukaryotes is responsible for the holdase activity of the protein PMID:37486705 since the high concentration of NaCl could abolish the holdase activity of Aha1, the electrostatic interactions mediated by those charged residues in Aha1's N-terminal extension are thus indicated to play a crucial role in the substrate recognition |
| GO:0001671 ATPase activator activity | IDA PMID:29127155 Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... | ACCEPT | Summary: IDA annotation for ATPase activator activity based on Woodford et al. 2017, which showed that AHSA1 activates HSP90 ATPase activity and competes with the inhibitory co-chaperone TSC1 for binding to the HSP90 middle domain. Phosphorylation of Aha1-Y223 increases its affinity for HSP90 and displaces TSC1, providing a regulatory switch for the chaperone cycle. This is direct experimental evidence for the core function of AHSA1. Reason: This is strong direct assay evidence for the core molecular function of AHSA1. The study demonstrates ATPase activation of HSP90 by AHSA1 and elucidates the regulatory mechanism involving phosphorylation of Y223 (PMID:29127155). Supporting Evidence: PMID:29127155 phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90 |
| GO:0032781 positive regulation of ATP-dependent activity | IDA PMID:29127155 Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... | ACCEPT | Summary: IDA annotation for positive regulation of ATP-dependent activity based on Woodford et al. 2017. AHSA1 stimulates the ATPase activity of HSP90, which is an ATP-dependent molecular chaperone. This annotation captures the regulatory biological process aspect of AHSA1's core function. The term is appropriate as AHSA1 positively regulates HSP90's ATP-dependent chaperone cycle. Reason: This annotation accurately captures the biological process corresponding to AHSA1's core molecular function. AHSA1 positively regulates HSP90's ATP-dependent chaperone cycle by stimulating its ATPase activity (PMID:29127155, PMID:12504007, PMID:27353360). Supporting Evidence: PMID:29127155 Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity ... prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1 |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | REMOVE | Summary: HDA annotation for cadherin binding from BHF-UCL, based on Guo et al. 2014, a large-scale quantitative proteomics study of the E-cadherin interactome using proximity biotinylation. AHSA1 was identified among 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. This is a high-throughput proximity labeling approach that detects proteins near E-cadherin, not necessarily direct binding partners. AHSA1 has no known functional relationship to cadherins, and its presence may reflect its abundance as a cytoplasmic chaperone co-factor. Reason: Cadherin binding is not a plausible molecular function for AHSA1, an HSP90 co-chaperone. The HDA evidence comes from proximity biotinylation proteomics (PMID:25468996), which identifies proteins in the general vicinity of E-cadherin, not direct binding partners. AHSA1 is an abundant cytosolic protein and likely a background hit. There is no functional relationship between AHSA1 and cadherin biology. |
| GO:0051879 Hsp90 protein binding | IPI PMID:29127155 Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facil... | ACCEPT | Summary: IPI annotation for Hsp90 protein binding based on Woodford et al. 2017, with interaction partner HSP90AA1 (P07900). This study demonstrated that AHSA1 binds to the middle domain of HSP90, and this interaction is enhanced by phosphorylation of Aha1-Y223. AHSA1 competes with TSC1 for HSP90 binding. This is the core molecular interaction of AHSA1. Reason: Hsp90 protein binding is the core molecular interaction of AHSA1, directly demonstrated by biochemical assays including binding competition with TSC1 (PMID:29127155). The interaction is mediated by the N-terminal domain of AHSA1 binding the HSP90 middle domain, and the C-terminal domain stabilizing the HSP90 N-terminal domain dimer. Supporting Evidence: PMID:29127155 The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. |
| GO:0005515 protein binding | IPI PMID:25486457 Middle domain of human Hsp90 isoforms differentially binds A... | MODIFY | Summary: IPI protein binding annotation from UniProt, based on Synoradzki and Bieganowski 2015, which demonstrated that Aha1 interacts preferentially with HSP90alpha (HSP90AA1) over HSP90beta (HSP90AB1), with the distinction depending on the middle domain of HSP90. The WITH column indicates interactions with both HSP90AA1 (P07900) and HSP90AB1 (P08238). This study provides insight into isoform-specific binding of AHSA1 to HSP90. Reason: The interactions detected are with both HSP90 isoforms, which is the core binding function of AHSA1. GO:0005515 is too vague; GO:0051879 (Hsp90 protein binding) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:25486457 the Hsp90 co-chaperone Aha1 interacts preferentially with Hsp90alpha. The distinction depends on the middle domain of Hsp90. |
| GO:0001671 ATPase activator activity | IDA PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | ACCEPT | Summary: IDA annotation for ATPase activator activity based on Woodford et al. 2016, which showed that AHSA1 competes with the inhibitory FNIP co-chaperones for HSP90 binding, providing a reciprocal regulatory mechanism. The paper demonstrates AHSA1's role as an ATPase activator in the context of competition with FNIP1/FNIP2. Reason: Direct experimental evidence for AHSA1's core function as an HSP90 ATPase activator. The study demonstrates that FNIPs compete with the activating co-chaperone Aha1 for binding to HSP90 (PMID:27353360), confirming AHSA1's role in activating the HSP90 ATPase cycle. Supporting Evidence: PMID:27353360 FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins |
| GO:0005515 protein binding | IPI PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | MODIFY | Summary: IPI protein binding annotation from UniProt, based on Woodford et al. 2016. The WITH column indicates interactions with HSP90AA1 (P07900) and FNIP1 (Q8NFG4). The interaction with HSP90AA1 is AHSA1's core function. The interaction with FNIP1 reflects the competitive binding relationship at the HSP90 middle domain rather than a direct AHSA1-FNIP1 interaction. Reason: The primary interaction detected is with HSP90AA1, which is AHSA1's core binding partner. GO:0005515 is too vague. The HSP90 binding is captured by GO:0051879. The interaction with FNIP1 (Q8NFG4) is indirect, reflecting competitive binding to HSP90 rather than direct AHSA1-FNIP1 binding. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:27353360 FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins |
| GO:0051087 protein-folding chaperone binding | IDA PMID:27353360 The FNIP co-chaperones decelerate the Hsp90 chaperone cycle ... | ACCEPT | Summary: IDA annotation for protein-folding chaperone binding based on Woodford et al. 2016, which demonstrated AHSA1 binding to HSP90. Since HSP90 is a protein-folding chaperone, this annotation is accurate and represents AHSA1's core interaction with HSP90. Reason: AHSA1 directly binds HSP90, which is a protein-folding chaperone. This annotation correctly captures AHSA1's core interaction and is supported by direct biochemical evidence (PMID:27353360). Supporting Evidence: PMID:27353360 FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: HDA annotation for extracellular exosome localization based on Gonzales et al. 2009, a large-scale proteomics study of urinary exosomes that identified 1132 proteins. AHSA1 was detected among these proteins. This is a high-throughput proteomics study, and the presence of AHSA1 in exosomes likely reflects its high abundance as a cytoplasmic protein rather than a specific exosome localization. Reason: AHSA1 was detected in urinary exosomes by mass spectrometry (PMID:19056867). While the detection is real, exosome localization is not a core function or localization of AHSA1. Many abundant cytoplasmic proteins are detected in exosome proteomics studies. This is a minor, non-functional localization. |
| GO:0001671 ATPase activator activity | IDA PMID:12504007 Activation of the ATPase activity of hsp90 by the stress-reg... | ACCEPT | Summary: IDA annotation for ATPase activator activity based on Panaretou et al. 2002, the foundational study that identified Aha1 as an activator of Hsp90 ATPase. This study demonstrated that Aha1 binds directly to Hsp90 and stimulates its ATPase activity in vitro, and is required for in vivo Hsp90-dependent activation of clients such as v-Src. This is the primary publication establishing AHSA1's core function. Reason: This is the foundational study that defined AHSA1's core function as an HSP90 ATPase activator (PMID:12504007). Direct experimental evidence including in vitro ATPase assays and in vivo client activation assays. Supporting Evidence: PMID:12504007 A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. |
| GO:0051087 protein-folding chaperone binding | IDA PMID:12504007 Activation of the ATPase activity of hsp90 by the stress-reg... | ACCEPT | Summary: IDA annotation for protein-folding chaperone binding based on Panaretou et al. 2002, which demonstrated that Aha1 binds directly to Hsp90. Since HSP90 is a protein-folding chaperone, this annotation correctly captures the core binding interaction of AHSA1. Reason: AHSA1 directly binds HSP90, a protein-folding chaperone, as demonstrated by the foundational study (PMID:12504007). This is a core interaction of AHSA1. Supporting Evidence: PMID:12504007 A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 |
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