Affinage

HSP90AA1

Heat shock protein HSP 90-alpha · UniProt P07900

Round 2 corrected
Length
732 aa
Mass
84.7 kDa
Annotated
2026-04-28
130 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSP90AA1 encodes the stress-inducible cytoplasmic molecular chaperone Hsp90α, an ATP-dependent homodimer that undergoes conformational cycles—driven by N-terminal ATP binding, middle-domain catalytic loop engagement, and N-terminal dimerization—to fold, stabilize, and activate a broad clientele of metastable proteins including kinases, steroid hormone receptors, and non-kinase substrates (PMID:9108479, PMID:22939624, PMID:34937942). Client loading occurs through an ordered multi-chaperone pathway: the Hsp70–Hop complex delivers partially unfolded clients into the Hsp90 lumen, and ATP-dependent closure followed by p23 binding enables client refolding to native conformation, as demonstrated by cryo-EM structures of the glucocorticoid receptor loading and maturation complexes (PMID:34937942, PMID:34937936, PMID:10786835). Chaperone activity is tuned by post-translational modifications—acetylation/deacetylation by HDAC6, Wee1-mediated tyrosine phosphorylation, S-nitrosylation at Cys589, K63-linked ubiquitination by FBXL6, and butyrylation at K754 by KAT8—each altering co-chaperone association, ATPase function, or client selectivity (PMID:15916966, PMID:20519952, PMID:34265086, PMID:32576198, PMID:37460462). Beyond chaperoning, Hsp90α possesses a structurally separable membrane-deforming amphipathic helix that promotes exosome release by driving multivesicular body–plasma membrane fusion, and facilitates TFEB nuclear translocation downstream of CDK5-regulated Ser595 phosphorylation to control autophagy and organismal lifespan (PMID:30193096, PMID:35941759).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    The structural basis of Hsp90's ATPase-driven chaperone cycle was unknown; the crystal structure of the N-terminal domain revealed a deep pocket that binds both ATP and geldanamycin, establishing that this single site governs both nucleotide hydrolysis and client protein refolding.

    Evidence X-ray crystallography of Hsp90 residues 9–232 with geldanamycin bound (Cell)

    PMID:9108479

    Open questions at the time
    • Full-length Hsp90 conformational cycle not yet resolved
    • Client-binding mechanism not addressed by N-domain structure alone
  2. 2000 High

    How clients are delivered to Hsp90 was unclear; crystal structures of the Hop TPR domains bound to C-terminal EEVD peptides of Hsp70 and Hsp90 established the molecular basis of the ordered Hsp70→Hop→Hsp90 relay that loads clients onto the chaperone.

    Evidence X-ray crystallography of Hop TPR1–Hsp70 and TPR2A–Hsp90 peptide complexes (Cell)

    PMID:10786835

    Open questions at the time
    • Structure of a full client-loaded Hsp70–Hop–Hsp90 complex not yet available
    • Mechanism of client transfer from Hsp70 to Hsp90 remained speculative
  3. 2000 High

    Whether Hsp90 chaperoning extended beyond steroid receptors to signal transduction kinases was unresolved; demonstration that Akt binds Hsp90 and that complex disruption triggers PP2A-mediated Akt dephosphorylation and apoptosis established kinase stabilization as a core Hsp90 function.

    Evidence Co-immunoprecipitation with deletion mutants, PP2A activity and apoptosis assays (PNAS)

    PMID:10995457

    Open questions at the time
    • Whether Hsp90 directly folds Akt versus merely shields it from phosphatases was unclear
    • Binding site on Hsp90 not mapped
  4. 2001 High

    The molecular switch between Hsp90-mediated folding and proteasomal degradation of clients was unknown; identification of CHIP as a TPR-containing E3 ligase that displaces p23 from Hsp90 and ubiquitylates the glucocorticoid receptor established a quality-control branch of the chaperone cycle.

    Evidence Co-IP, ubiquitylation assay, GR transactivation, proteasome inhibitor experiments (Nature Cell Biology)

    PMID:11146632

    Open questions at the time
    • Structural basis of CHIP–Hsp90 competition with p23 not determined
    • Generality across non-receptor clients untested at this point
  5. 2003 High

    The catalytic mechanism of Hsp90's ATPase was incompletely understood; determination of the middle-domain structure and mutagenesis revealed a catalytic loop essential for ATP hydrolysis that functions cooperatively with N-terminal dimerization, and also mediates client recognition.

    Evidence Crystal structure of Hsp90 middle domain, ATPase assays, mutagenesis

    PMID:14529383

    Open questions at the time
    • Full-length closed-state structure not yet available
    • How the middle domain recognizes diverse clients structurally unresolved
  6. 2003 High

    Whether Hsp90 participates in organelle biogenesis was unknown; demonstration that Hsp90 and Hsp70 dock onto the mitochondrial import receptor Tom70 via a TPR domain and deliver preproteins in an ATPase-dependent manner established a chaperone-mediated mitochondrial targeting pathway.

    Evidence Co-immunoprecipitation, import assays with ATPase mutants, crosslinking (Cell)

    PMID:12526792

    Open questions at the time
    • Which mitochondrial preproteins require Hsp90 versus Hsp70 alone was unclear
    • Whether this pathway operates in vivo in mammalian systems not directly tested
  7. 2005 High

    How post-translational modifications regulate Hsp90 chaperone activity was largely unexplored; discovery that HDAC6 deacetylates Hsp90 and that hyperacetylation causes p23 dissociation and loss of glucocorticoid receptor maturation established acetylation as a key regulatory switch.

    Evidence HDAC6 knockout/knockdown, acetylation assay, GR ligand-binding, nuclear translocation and transcriptional reporter (Molecular Cell); corroborated by reciprocal gain/loss-of-function in leukemia cells (JBC)

    PMID:15916966 PMID:15937340

    Open questions at the time
    • Specific acetylated lysine residues on Hsp90 not yet mapped at this stage
    • Whether other HDACs contribute was unclear
  8. 2010 High

    Cell-cycle regulation of Hsp90 was uncharacterized; identification of Wee1/Swe1-mediated tyrosine phosphorylation of Hsp90 (Y24) that modulates ATPase activity, geldanamycin binding, and G2/M checkpoint control established a direct link between cell cycle kinases and chaperone function.

    Evidence Phosphorylation assays, yeast genetics with Y24F non-phosphorylatable mutant, cell cycle analysis (Cell Cycle)

    PMID:20519952

    Open questions at the time
    • Whether Wee1-mediated phosphorylation of Hsp90 operates identically in mammalian systems was not confirmed
    • Client specificity of the phosphorylated form not tested
  9. 2012 High

    What determines Hsp90 client selectivity among the kinome was a central open question; a proteome-scale survey revealed that thermodynamic instability of the kinase—not primary sequence—dictates Hsp90 binding affinity, while Cdc37 provides kinase-family specificity.

    Evidence Quantitative proteomics interaction survey across most human kinases, small-molecule stabilization experiments (Cell)

    PMID:22939624

    Open questions at the time
    • Structural basis for how Hsp90 senses thermodynamic instability unknown
    • Whether instability-driven selection applies to non-kinase clients untested
  10. 2015 High

    How Cdc37 physically couples kinase clients to Hsp90 was structurally unresolved; NMR mapping showed Cdc37's N-terminal region binds the Hsp90 middle domain while its C-terminal region contacts and displaces nucleotide from kinase clients, revealing cooperative ternary complex assembly.

    Evidence NMR spectroscopy, in vitro reconstitution, mutagenesis (JBC)

    PMID:26511315

    Open questions at the time
    • High-resolution structure of the full ternary complex not yet available
    • Variation in Cdc37 contributions across different kinase clients acknowledged but not structurally explained
  11. 2017 High

    Whether Hsp90 has functions beyond protein folding was unclear; discovery of an amphipathic helix exposed in the open dimer conformation that deforms lipid membranes and promotes multivesicular body–plasma membrane fusion for exosome release established a chaperone-independent role in vesicle trafficking.

    Evidence Cell-free MVB fusion assay, in vivo exosome measurements, amphipathic helix mutagenesis, drug-induced conformational trapping (Molecular Cell)

    PMID:30193096

    Open questions at the time
    • Whether this membrane function is regulated by the same PTMs that control chaperone activity is unknown
    • Relevance to in vivo exosome biology in disease settings not tested
  12. 2021 High

    The structural mechanism of client loading and maturation by the full Hsp90 machinery was unresolved at atomic detail; back-to-back cryo-EM structures of the GR-loading complex (GR–Hsp90–Hsp70–Hop with partially unfolded GR) and the GR-maturation complex (GR–Hsp90–p23 with refolded, ligand-bound GR) revealed the complete conformational trajectory from client capture to release.

    Evidence Cryo-electron microscopy of both complexes (Nature, two papers)

    PMID:34937936 PMID:34937942

    Open questions at the time
    • Kinase client loading/maturation structural intermediates remain unresolved
    • Dynamic transitions between loading and maturation states not captured
  13. 2021 High

    How specific PTMs redirect Hsp90 toward pathological signaling was unclear; identification of iNOS-mediated S-nitrosylation at Cys589 showed that this modification enhances TGFβR2 binding to Hsp90, increases SMAD3 phosphorylation and nuclear translocation, and promotes cardiac fibrosis, reversible by site-specific mutagenesis in vivo.

    Evidence Biotin-switch assay, MS site identification (Cys589), AAV-mediated Cys589 mutagenesis in TAC mouse model (British J Pharmacol)

    PMID:34265086

    Open questions at the time
    • Whether other S-nitrosylation sites on Hsp90 have distinct functional consequences is unknown
    • Structural mechanism by which SNO-Cys589 enhances TGFβR2 binding not determined
  14. 2022 High

    Whether Hsp90 directly participates in transcription factor nuclear import and autophagy regulation was unknown; demonstration that HSP90AA1 facilitates TFEB nuclear translocation—inhibited by CDK5-mediated phosphorylation at Ser595—linked Hsp90 to autophagy induction and longevity, conserved in C. elegans.

    Evidence CDK5 phospho-mutant analysis, co-IP, nuclear fractionation, autophagy and C. elegans lifespan assays (Autophagy)

    PMID:35941759

    Open questions at the time
    • Mechanism by which Hsp90 physically escorts TFEB to the nucleus not resolved
    • Whether other chaperone clients compete with TFEB for Hsp90 binding at this site is unknown
  15. 2023 High

    How PP5 phosphatase is activated and directed toward kinase clients within the Hsp90 complex was structurally unresolved; cryo-EM of the PP5–Hsp90–Cdc37–CRaf complex revealed that Hsp90 both activates PP5 and scaffolds its positioning to dephosphorylate CRaf, with steric constraints dictating that kinase release precedes Cdc37 dephosphorylation.

    Evidence Cryo-EM structure determination, phosphatase activity assays (Nature Communications)

    PMID:37069154

    Open questions at the time
    • Whether the ordered dephosphorylation mechanism applies to all kinase clients is untested
    • Dynamics of kinase release from the complex not captured
  16. 2023 Medium

    The expanding repertoire of Hsp90 regulatory modifications was extended by identification of butyrylation at K754 (written by KAT8, erased by HDAC11), and K48-linked deubiquitination by USP14 that stabilizes HSP90AA1 protein levels, linking non-canonical acylation and ubiquitin editing to drug resistance and disease.

    Evidence Butyrylome MS profiling with writer/eraser identification (Cell Discovery); K48-ubiquitin linkage analysis with USP14 gain/loss-of-function in NAFLD models (Cell Death & Disease)

    PMID:37460462 PMID:37633951

    Open questions at the time
    • How butyrylation at K754 mechanistically alters Hsp90 chaperone activity or client selectivity is unknown
    • Whether USP14-mediated stabilization is tissue-specific remains to be tested
    • Independent replication of butyrylation findings needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for how Hsp90 senses client thermodynamic instability to set binding affinity; full structural trajectories for kinase client folding comparable to the GR cycle; how the multiple PTMs (acetylation, phosphorylation, S-nitrosylation, ubiquitination, butyrylation) are integrated combinatorially; and the physiological significance and regulation of Hsp90's membrane-deforming function in vivo.
  • No structural model for instability-sensing mechanism
  • Kinase client cryo-EM loading/maturation cycle incomplete
  • Combinatorial PTM code uncharacterized
  • In vivo regulation of amphipathic helix exposure unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 9 GO:0140657 ATP-dependent activity 4 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005829 cytosol 6 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
AKT1CDC37HDAC6HSPA1ANOS3PTGES3STIP1STUB1
Complex memberships
Hsp90–Cdc37 (kinase chaperone complex)Hsp90–Hsp70–Hop (loading complex)Hsp90–PP5–Cdc37–kinase complexHsp90–p23 (maturation complex)

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Crystal structure of the N-terminal geldanamycin-binding domain of Hsp90 (residues 9-232) revealed a deep pocket (15 Å) that binds geldanamycin in a turn conformation resembling a polypeptide substrate, demonstrating that this pocket is both the ATP-binding site and the site responsible for conformational maturation/refolding of client proteins. X-ray crystallography Cell High 9108479
1998 Hsp90 dynamically associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists (VEGF, histamine, fluid shear stress); binding of Hsp90 to eNOS enhances eNOS activation, and inhibition of Hsp90 attenuates agonist-stimulated nitric oxide production and endothelium-dependent vessel relaxation. Co-immunoprecipitation, pharmacological inhibition, isolated blood vessel functional assay Nature High 9580552
2000 Akt kinase forms a complex with Hsp90 in vivo; the Akt residues 229–309 bind to Hsp90β residues 327–340. Disruption of the Akt–Hsp90 interaction leads to PP2A-mediated dephosphorylation and inactivation of Akt, increasing apoptotic sensitivity. Co-immunoprecipitation with deletion mutants, PP2A activity assay, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 10995457
2000 The adaptor protein Hop (Sti1) bridges Hsp70 and Hsp90 through its TPR1 domain binding the C-terminal heptapeptide of Hsp70 and TPR2A domain binding the C-terminal pentapeptide of Hsp90, both ending in EEVD; crystal structures show peptides in extended conformation with the C-terminal aspartate acting as a two-carboxylate anchor, explaining ordered assembly of the Hsp70–Hsp90 multichaperone complex. X-ray crystallography of TPR domain–peptide complexes Cell High 10786835
2001 CHIP (carboxyl terminus of Hsc70-interacting protein) interacts directly with a TPR acceptor site on Hsp90, displaces the co-chaperone p23, and remodels Hsp90 heterocomplexes to favour ubiquitylation and proteasomal degradation of the glucocorticoid receptor client, establishing CHIP as a molecular switch between protein folding and degradation. Co-immunoprecipitation, ubiquitylation assay, GR transactivation assay, proteasome inhibitor experiments Nature cell biology High 11146632
2001 Pim-1 serine/threonine kinase physically interacts with Hsp90α and Hsp90β; treatment with the Hsp90-specific inhibitor geldanamycin induces rapid proteasomal degradation of Pim-1 and reduces its kinase activity, demonstrating Hsp90 is required for Pim-1 stabilization and function. Co-immunoprecipitation, geldanamycin treatment, kinase activity assay Biochemical and biophysical research communications Medium 11237709
2001 Hsp90N, a novel Hsp90 family member lacking the ansamycin-binding domain and containing a myristylation signal, binds Raf-1 with higher affinity than canonical Hsp90 and does not associate with the co-chaperone p50(Cdc37); stable transfection of Hsp90N activates Raf and ERK kinases, recruits Raf to the membrane, and causes neoplastic transformation in a Ras-independent manner. Protein identification, co-immunoprecipitation, kinase activity assay, stable transfection, transformation assays The Journal of biological chemistry Medium 11751906
2003 Cytosolic Hsp90 and Hsp70 dock onto a specialized TPR domain in the mitochondrial import receptor Tom70; this interaction delivers preproteins to Tom70 for membrane translocation in an Hsp90 ATPase-dependent manner, defining a novel chaperone-mediated targeting mechanism. Co-immunoprecipitation, import assay with Hsp90 ATPase mutants, crosslinking Cell High 12526792
2003 Hsp90 associates with survivin via the Hsp90 ATPase domain interacting with the survivin baculovirus IAP repeat; disruption of the survivin–Hsp90 complex by geldanamycin or antibody causes proteasomal degradation of survivin, mitochondrial-dependent apoptosis, and mitotic defects. Co-immunoprecipitation, domain mapping, proteasome inhibitor assay, apoptosis and cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 14614132
2003 The middle domain of Hsp90 contains a catalytic loop with key residues essential for ATP hydrolysis; ATP hydrolysis depends on a rate-limiting step involving N-terminal dimerization coupled with association of the middle domain catalytic loop with the N-terminal domains; the middle domain also mediates client protein recognition through substrate active-site interactions. Crystal structure of middle domain, biochemical ATPase assays, mutagenesis Current cancer drug targets High 14529383
2004 Novobiocin binds a C-terminal nucleotide-binding site on Hsp90 and induces a distinct protease-resistant conformation of the C-terminal domain; this conformational change causes dissociation of Hsp90 and Cdc37 from the client kinase HRI while leaving p23, FKBP52, and PP5 associated, inhibiting Hsp90/Cdc37-dependent HRI kinase maturation; this conformation was proposed to represent a client-release state. Proteolytic fingerprinting, reticulocyte lysate maturation assay, domain binding studies Biochemistry Medium 15209518
2004 Evolutionary tracing and protein-protein docking identified a putative interface between the Hsp90 N-terminal ATP-binding domain and co-chaperone p23; ATP-induced N-domain dimerization is proposed to expose hydrophobic surface via reorientation of helix α1 and lid residues 10–27, triggering p23 binding in an ATP-dependent manner. Evolutionary tracing analysis, computational protein-protein docking FASEB journal Low 15173105
2005 HDAC6 functions as an Hsp90 deacetylase; inactivation of HDAC6 leads to Hsp90 hyperacetylation, dissociation of p23 co-chaperone, loss of chaperone activity, and defective glucocorticoid receptor maturation (impaired ligand binding, nuclear translocation, and transcriptional activation). HDAC6 knockout/knockdown, acetylation assay, GR ligand-binding assay, nuclear translocation imaging, transcriptional reporter Molecular cell High 15916966
2005 HDAC6 co-immunoprecipitates with Hsp90 in leukemia cells; siRNA knockdown of HDAC6 induces Hsp90 acetylation, inhibits Hsp90 ATP binding, reduces chaperone association with client proteins (Bcr-Abl, AKT, c-Raf), and promotes their polyubiquitylation and degradation; conversely, HDAC6 overexpression rescues these effects. Co-immunoprecipitation, siRNA knockdown, HDAC6 overexpression, ATP-binding assay, ubiquitylation assay The Journal of biological chemistry High 15937340
2010 Wee1/Swe1 kinase mediates cell cycle-dependent tyrosine phosphorylation of Hsp90; this phosphorylation affects geldanamycin binding, Hsp90 ATPase activity, and the ability to chaperone a selected group of kinase clients; yeast expressing non-phosphorylatable Hsp90-Y24F undergo premature nuclear division insensitive to G2/M checkpoint arrest, and Wee1 association with Hsp90 depends on this phosphorylation. Phosphorylation assays, yeast genetics (non-phosphorylatable mutant), cell cycle analysis, ATPase assay Cell cycle (Georgetown, Tex.) High 20519952
2011 Hsp90 regulates the cellular pool of Sir2p (yeast sirtuin) and thereby controls telomere silencing and mating type silencing; both Hsp90 deficiency and Hsp90 overexpression reduce Sir2p levels, demonstrating that Hsp90 homeostasis is required for Sir2p stability independently of the co-chaperone Sba1. Temperature-sensitive Hsp90-deficient yeast strain, Hsp90 overexpression, silencing assays PloS one Medium 21829731
2011 Hsp90 directly binds and stabilizes the Y-family DNA polymerase REV1 in vivo and in vitro; Hsp90 inhibition reduces REV1 protein levels via proteasomal degradation, suppresses UV-induced mutagenesis, disrupts the REV1–monoubiquitinated PCNA interaction, and suppresses UV-induced REV1 focus formation, establishing Hsp90 as a regulator of translesion DNA synthesis. Co-immunoprecipitation in vivo and in vitro, Hsp90 inhibitor treatment, proteasome inhibitor rescue, mutation frequency assay, immunofluorescence focus formation Molecular and cellular biology High 21690293
2012 Systematic quantitative survey of most human kinases, transcription factors, and E3 ligases revealed that HSP90 associates preferentially with intrinsically unstable kinases rather than specific sequence motifs; CDC37 specifically recognizes the kinase family and provides selectivity, while thermodynamic instability determines binding affinity within the kinase family; stabilization of kinases in either active or inactive conformations with small molecules decreased HSP90 association. Quantitative proteomics-based interaction survey, small molecule stabilization experiments Cell High 22939624
2012 STAT3 directly interacts with Hsp90β with high affinity as measured by surface plasmon resonance; the interaction is independent of STAT3 phosphorylation at Y705 but requires an intact DNA-binding domain (R414/R417); mutation of the DNA-binding domain reduces interaction with Hsp90 in vitro and decreases co-localization with Hsp90α/β in MCF7 cells. Surface plasmon resonance, site-directed mutagenesis, co-immunoprecipitation, confocal microscopy co-localization IUBMB life Medium 22271514
2013 Nitration of Hsp90 at a single tyrosine residue (position 33 or 56) is sufficient to induce motor neuron death via P2X7 receptor-dependent activation of the Fas pathway; nitrotyrosine at these positions confers a toxic gain of function; nitrated Hsp90 immunoreactivity was found in ALS patient motor neurons and animal models. Site-specific nitration, P2X7 receptor pharmacology, Fas pathway analysis, immunohistochemistry in patient tissue Proceedings of the National Academy of Sciences of the United States of America High 23487751
2014 Terazosin binds phosphoglycerate kinase 1 (Pgk1) and activates its enzymatic activity; the ATP generated by Pgk1 enhances the chaperone activity of Hsp90 (an ATPase known to associate with Pgk1), which upon activation promotes multistress resistance in rodent models of stroke and sepsis. Enzymology assays, X-ray crystallography of Pgk1-terazosin complex, co-association studies, in vivo rodent models Nature chemical biology Medium 25383758
2015 HSP90AA1-specific knockdown inhibits proliferation and increases apoptosis of ovarian cancer SKOV3 cells; overexpression of HSP90AA1 decreases cisplatin sensitivity and partially rescues cell survival under cisplatin treatment, establishing HSP90AA1 as required for SKOV3 cell survival and chemoresistance. RNAi knockdown, overexpression, MTT assay, FACS apoptosis analysis Molecular biology reports Medium 23135731
2015 HSP90AA1 is the stress-inducible Hsp90 isoform encoded by the HSP90AA1 gene; it is regulated differently from constitutively expressed Hsp90β due to differences in non-coding sequence (allowing specific transcription factor interactions including via heat shock elements) and subtle amino acid differences enabling unique post-translational modifications. Gene regulation analysis, sequence comparison, transcription factor interaction studies Gene Medium 26071189
2015 Co-chaperone Cdc37 binds the middle domain of Hsp90 via its N-terminal region; the C-terminal part of Cdc37 binds kinase client proteins (B-Raf, Erk2) and displaces nucleotide from the kinase; cooperative formation of the ternary Hsp90–Cdc37–kinase complex occurs with multiple distinct interaction sites, with variation in Cdc37 domain contributions between different kinases. NMR spectroscopy for binding site mapping, in vitro reconstitution of ternary complex, mutagenesis The Journal of biological chemistry High 26511315
2016 Hsp90 facilitates Ser-621 phosphorylation of CRAF kinase (assisted by Cdc37), protecting it from degradation; however, post-folding CRAF stability becomes insensitive to Hsp90 inhibition while physical association persists; elevated Hsp90 promotes MAPK signaling by activating CRAF; Hsp90 binding to CRAF (independent of Hsp90 ATPase activity) precedes Ras–CRAF association and facilitates actin recruitment to CRAF for efficient Ras–CRAF interaction. Co-immunoprecipitation, phosphorylation assays, Hsp90 inhibitor treatment, overexpression, MAPK pathway activation assays The Journal of biological chemistry Medium 27703006
2016 miR-1 directly interacts with the 3'UTR of Hsp90aa1 mRNA at nucleotides 310–315, inhibiting Hsp90aa1 expression post-transcriptionally; in a rat cardiac ischemia/reperfusion model, miR-1 is downregulated post-I/R allowing recovery of Hsp90aa1 protein; overexpression of Hsp90aa1 attenuates OGD-induced cardiomyocyte apoptosis. Dual luciferase reporter assay, miR-1 mimic/inhibitor transfection, rat I/R model, OGD apoptosis assay Scientific reports Medium 27076094
2016 The Cdc37 co-chaperone, working with Hsp90AA1 (Hsp90α), stabilizes the rabies virus phosphoprotein (P) — a non-kinase viral client — during infection; activity inhibition or knockdown of Cdc37 and Hsp90AA1 increases P protein instability; Cdc37 (phosphorylated or unphosphorylated on Ser13) loads P onto the Hsp90 machinery; allosteric regulation by Cdc37–Hsp90 interaction controls Hsp90 conformational switching. Co-immunoprecipitation, knockdown, overexpression, virus titer assay, phospho-mutant Cdc37 analysis Scientific reports Medium 27251758
2017 Hsp90 has an evolutionarily conserved amphipathic helix that enables direct interaction with and deformation of lipid membranes; this membrane-deforming function promotes fusion of multivesicular bodies (MVBs) with the plasma membrane to release exosomes; the open dimer conformation of Hsp90 (stabilized by mutations or drugs) exposes this helix and allows MVB fusion, while the closed state blocks it; this function is structurally separable from chaperone activity. Cell-free MVB fusion system, in vivo exosome measurements, mutagenesis of amphipathic helix, drug-induced conformational trapping Molecular cell High 30193096
2018 HSP90AA1 promotes drug resistance in osteosarcoma by inducing autophagy through the PI3K/Akt/mTOR pathway and inhibiting apoptosis through the JNK/P38 pathway; shRNA knockdown of HSP90AA1 restores chemosensitivity both in vitro and in a NOD/SCID xenograft model. shRNA knockdown, lentiviral overexpression, western blot for LC3/autophagy markers, transmission electron microscopy, mRFP-GFP-LC3 flux assay, in vivo xenograft Journal of experimental & clinical cancer research Medium 30153855
2018 Hsp90AA1 interacts with phospholipid membranes with high affinity, penetrating ~10.7 Å into the hydrocarbon core primarily through its C-terminal domain (CTD); this interaction involves conformational change (loss of α-helical structure); E. coli cells overexpressing Hsp90AA1 or Hsp90AA1-CTD show better membrane integrity after thermal stress, and Hsp90AA1 stabilizes membrane lipids against leakage. Depth-dependent fluorescence quenching with brominated lipids, circular dichroism, domain binding assays, scanning electron microscopy, liposome leakage assay Biochimica et biophysica acta. Biomembranes Medium 30517848
2019 In both E. coli and yeast, Hsp90 directly interacts with Hsp70 via a site in the middle domain of Hsp90 and the J-protein binding site of Hsp70 (DnaK); J-protein promotes this Hsp70–Hsp90 interaction in the presence of ATP by converting Hsp70 to the ADP-bound conformation. Chemical crosslinking experiments, mutational analysis in E. coli and yeast Journal of molecular biology Medium 31125567
2020 FBXL6, an SCF complex F-box protein, is the ubiquitin ligase for HSP90AA1; FBXL6 promotes K63-linked ubiquitination of HSP90AA1, which stabilizes (rather than degrades) it; stabilized HSP90AA1 prevents c-MYC degradation; activated c-MYC in turn transcriptionally induces FBXL6 expression, forming a positive feedback loop in hepatocellular carcinoma. IP/MS identification of FBXL6 interactors, co-immunoprecipitation, in vivo ubiquitination assay, luciferase reporter, ChIP assay, xenograft model Cell communication and signaling High 32576198
2021 Cryo-EM structure of the GR-loading complex (GR–Hsp90–Hsp70–Hop) revealed two Hsp70 molecules (one delivering GR, one scaffolding Hop); GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70, and Hop; Hop interacts with all components including GR and poises Hsp90 for subsequent ATP hydrolysis. Cryo-electron microscopy structure determination Nature High 34937942
2021 Cryo-EM structure of the GR-maturation complex (GR–Hsp90–p23) showed the GR ligand-binding domain restored to a folded, ligand-bound conformation while threaded through the Hsp90 lumen; p23 directly stabilizes native GR via a C-terminal helix, enhancing ligand binding; this contrasts with the unfolded state of kinase clients in Hsp90 complexes, showing client-specific folding outcomes. Cryo-electron microscopy structure determination Nature High 34937936
2021 S-nitrosylation of HSP90 at cysteine 589 (identified by mass spectrometry) stimulates binding of TGFβ receptor 2 to HSP90, leading to increased SMAD3 phosphorylation and nuclear translocation and promoting cardiac fibrosis; iNOS is the enzyme responsible for generating SNO-HSP90; genetic (Cys589 mutation via AAV) or pharmacological (iNOS inhibitor) blockade of SNO-HSP90 reduces fibrosis in vivo. Biotin-switch assay, mass spectrometry for S-nitrosylation site identification, site-directed mutagenesis (Cys589), AAV delivery in TAC mouse model, co-immunoprecipitation, SMAD3 phosphorylation and nuclear translocation assay British journal of pharmacology High 34265086
2022 HSP90AA1 promotes nuclear localization of TFEB (transcription factor EB) and thereby induces autophagy and extends lifespan; CDK5 phosphorylates HSP90AA1 at Ser595 under basal conditions, which inhibits HSP90AA1 and disrupts its binding to TFEB, impeding TFEB nuclear localization; pro-autophagy signaling reduces CDK5 activity, freeing HSP90AA1 to facilitate TFEB nuclear translocation; this regulatory axis is conserved in C. elegans lifespan extension. Phosphorylation assays (CDK5 phospho-mutants), co-immunoprecipitation, nuclear fractionation, autophagy induction assays, C. elegans lifespan assay Autophagy High 35941759
2022 DAB2IP negatively regulates HSP90AA1 expression in colorectal cancer; mechanistically, DAB2IP promotes apoptosis through an HSP90AA1/SRP9/ASK1/JNK signaling axis; loss of DAB2IP leads to elevated HSP90AA1, increased SRP9 expression, and suppressed apoptotic signaling. Bioinformatic analysis, in vitro and in vivo experiments, flow cytometry for apoptosis, pathway inhibitor studies BMC cancer Medium 35590292
2023 Cryo-EM structure of PP5 in complex with Hsp90:Cdc37:CRaf revealed that Hsp90 both activates PP5 phosphatase and scaffolds its association with bound CRaf to dephosphorylate phosphorylation sites neighboring the kinase domain; Hsp90-bound kinase sterically inhibits Cdc37 dephosphorylation, indicating kinase release must precede Cdc37 dephosphorylation. Cryo-electron microscopy structure determination, phosphatase activity assays, steric clash analysis Nature communications High 37069154
2023 USP14 deubiquitinase stabilizes HSP90AA1 by decreasing its K48-linked ubiquitination, thereby preventing proteasomal degradation; elevated HSP90AA1 in turn promotes CYP2E1 protein accumulation, exacerbating oxidative stress and inflammation in NAFLD progression. Immunoprecipitation, ubiquitination analysis (K48-linkage specific), USP14 overexpression/knockdown in vivo and in vitro, CYP2E1 functional assays Cell death & disease Medium 37633951
2023 Lysine 754 of HSP90 undergoes butyrylation (Kbu), a novel acylation modification; this modification is written by KAT8 and erased by HDAC11, with SDCBP increasing Kbu by competitively binding HDAC11; Kbu of HSP90 K754 leads to HSP90 overexpression and contributes to 5-FU resistance in esophageal squamous cell carcinoma. Butyrylome profiling by mass spectrometry, gain/loss-of-function experiments, competitive binding assay for SDCBP/HDAC11 Cell discovery Medium 37460462
2015 HSP90AA1 on the cell surface acts as a receptor for avibirnavirus by binding to the viral capsid protein VP2; this binding induces autophagy and inactivates the AKT-MTOR pathway; siRNA knockdown of HSP90AA1, AKT, or MTOR inhibits autophagy during infection; autophagy inhibition (not induction) enhances viral replication, indicating that HSP90AA1-triggered autophagy limits infection. Transmission electron microscopy, confocal microscopy for autolysosomes, LC3-II western blot, RNA interference knockdown, virus titer assay Autophagy Medium 25714412

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Targeting the dynamic HSP90 complex in cancer. Nature reviews. Cancer 1251 20651736
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
1997 Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 1184 9108479
2017 The HSP90 chaperone machinery. Nature reviews. Molecular cell biology 1160 28429788
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 1016 10786835
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