Affinage

CDC37

Hsp90 co-chaperone Cdc37 · UniProt Q16543

Length
378 aa
Mass
44.5 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC37 is a kinase-specific cochaperone of HSP90 that functions as a molecular scaffold to recruit, stabilize, and regulate the maturation of a large fraction of the protein kinome. CDC37 recognizes client kinases through their N-lobe glycine-rich loop (GXGXXG motif), locally unfolds them into a metastable state, and loads them onto HSP90; cryo-EM structures of HSP90–CDC37–CDK4 and HSP90–CDC37–RAF1 ternary complexes reveal that client kinases are held with their N- and C-lobes completely separated, while CDC37 mimics part of the kinase N-lobe and an inserted arginine suppresses HSP90 ATPase activity to arrest the chaperone cycle until client release (PMID:27339980, PMID:36055235, PMID:14718169). CK2-mediated phosphorylation of CDC37 at Ser13 is essential for client kinase binding and HSP90 recruitment, and PP5/Ppt1-catalyzed dephosphorylation of pSer13 within assembled complexes completes a regulatory phosphorylation–dephosphorylation cycle that governs client maturation and release (PMID:15082798, PMID:18922470). Through this mechanism, CDC37 controls the stability and activity of diverse signaling kinases including CDK4/6, RAF1, AKT, IKK, RIP3, ULK1, Aurora B, JAK1, PINK1, and LKB1, thereby impacting cell cycle progression, MAPK and NF-κB signaling, necroptosis, mitophagy, and kinase quality control (PMID:8666233, PMID:10022854, PMID:11864612, PMID:25852146, PMID:21855797, PMID:17242065).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 High

    Establishing that CDC37 is required for CDK function resolved how a non-cyclin factor could control cell-cycle kinase activity: yeast Cdc37 is needed for Cdc28 to associate with G1 and mitotic cyclins.

    Evidence Temperature-sensitive cdc37-1 yeast mutant analysis with co-immunoprecipitation and kinase assays

    PMID:7753858

    Open questions at the time
    • Mechanism of how Cdc37 promotes cyclin–CDK association was unknown
    • Whether Cdc37 acted directly on Cdc28 or indirectly was unresolved
  2. 1996 High

    Identifying mammalian CDC37 as a kinase-targeting subunit of HSP90 that specifically binds CDK4 (not CDK2/3/5) established the paradigm of CDC37 as a kinase-selective cochaperone rather than a general chaperone cofactor.

    Evidence Co-immunoprecipitation, insect cell reconstitution, geldanamycin inhibition, yeast two-hybrid (two independent studies)

    PMID:8666233 PMID:8703009

    Open questions at the time
    • The structural basis for kinase selectivity was unknown
    • Whether CDC37 had intrinsic chaperone activity independent of HSP90 was untested
  3. 1997 High

    Demonstrating that CDC37 possesses autonomous chaperone activity (independent of HSP90) clarified that it is not merely an adaptor but actively maintains kinase clients in folding-competent states.

    Evidence In vitro β-galactosidase refolding assay and in vivo complementation of Hsp90 deficiency for v-Src but not glucocorticoid receptor

    PMID:9242486

    Open questions at the time
    • The domain(s) responsible for intrinsic chaperone activity were not mapped
    • How CDC37 discriminates kinases from non-kinase clients at a structural level was unclear
  4. 1999 High

    Showing that a ternary RAF1–CDC37–HSP90 complex is required for RAF1 kinase activation extended CDC37 function beyond CDKs to the MAPK signaling pathway and established the ternary complex as the functional unit.

    Evidence Dominant-negative CDC37 mutant unable to recruit HSP90 blocks RAF1/MAPK activation in Sf9 cells

    PMID:10022854

    Open questions at the time
    • How CDC37 contacts RAF1 structurally was unknown
    • Whether all kinase clients require the same ternary complex architecture was untested
  5. 2000 High

    Pulse-chase experiments revealing that Cdc37 stabilizes kinases during rather than after translation established a co-translational quality-control role, distinguishing it from purely post-translational chaperone functions.

    Evidence Pulse-chase labeling in yeast cdc37 temperature-sensitive mutant for Cdc28 and Cak1 stability

    PMID:10629030

    Open questions at the time
    • Whether CDC37 directly binds nascent kinase chains on ribosomes was not shown
    • The extent of kinome dependence on CDC37 was not yet quantified
  6. 2002 High

    Extension of CDC37–HSP90 client repertoire to AKT, IKK, and viral RT demonstrated that CDC37 is a broad kinase cochaperone governing diverse signaling pathways (PI3K/AKT, NF-κB) and even non-kinase clients with kinase-like folds.

    Evidence Co-immunoprecipitation, size-exclusion chromatography, geldanamycin/proteasome inhibitor treatment, ubiquitination assays across multiple client kinases

    PMID:11864612 PMID:11986322 PMID:12176997

    Open questions at the time
    • How CDC37 distinguishes hundreds of kinase clients at a molecular level was still unknown
    • The stoichiometry and structure of each ternary complex was unresolved
  7. 2002 High

    Discovering that CDC37 suppresses HSP90 ATPase activity (analogous to Hop/Sti1) revealed a key regulatory mechanism: CDC37 arrests the HSP90 conformational cycle to maintain the complex in a client-loading-competent state.

    Evidence ATPase activity assays with purified proteins, analytical ultracentrifugation showing dimeric CDC37 binding

    PMID:11916974

    Open questions at the time
    • The structural basis for ATPase inhibition was not yet resolved at atomic detail
  8. 2003 High

    Identification of CK2-mediated Ser13 phosphorylation as essential for CDC37 function in HSP90–kinase complexes established the first regulatory modification controlling cochaperone–client interaction.

    Evidence In vitro CK2 kinase assays, S13A/S13E mutagenesis disrupting HSP90–kinase complex assembly, validated in two independent studies

    PMID:12930845 PMID:15082798

    Open questions at the time
    • The phosphatase that reverses Ser13 phosphorylation was unknown
    • How phosphorylation structurally alters CDC37 was not determined
  9. 2004 High

    The crystal structure of HSP90 N-domain bound to CDC37 revealed the atomic mechanism of ATPase suppression: CDC37 inserts an arginine into the HSP90 ATP-binding pocket and locks the lid in an open conformation, preventing N-terminal dimerization.

    Evidence X-ray crystallography of the HSP90–CDC37 core complex with ATPase assay and mutagenesis validation

    PMID:14718169

    Open questions at the time
    • How client kinase is positioned in the ternary complex was not visible in this binary structure
    • Full-length complex architecture remained unknown
  10. 2004 High

    Mapping the client-recognition determinant to the kinase N-lobe glycine-rich loop (GXGXXG motif) resolved how CDC37 achieves kinase specificity: mutations in Gly-15/Gly-18 of CDK4 abolish CDC37 binding.

    Evidence Site-directed mutagenesis of CDK4 and RAF1 glycine-rich loop residues with in vitro and cellular binding assays

    PMID:14701845

    Open questions at the time
    • Why some kinases with intact G-loops are not CDC37 clients was unexplained
    • The contribution of kinase C-lobe determinants was only partially characterized
  11. 2006 High

    EM reconstruction of the HSP90–CDC37–CDK4 ternary complex provided the first three-dimensional view of how all three components are arranged, showing Cdc37 bridging HSP90 and kinase and suggesting coupling to the HSP90 ATPase cycle.

    Evidence Single-particle electron microscopy with analytical ultracentrifugation and mass spectrometry

    PMID:16949366

    Open questions at the time
    • Resolution was insufficient to identify secondary-structure contacts or kinase unfolding state
  12. 2006 High

    Phage-display and chimeric-kinase experiments showed that CDC37 recognizes the GXFG motif in the glycine-rich loop and that C-lobe/C-terminal determinants dictate differential affinity (CDK4 vs CDK2), explaining how selectivity arises beyond the conserved N-lobe.

    Evidence Phage display, LC-MS/MS, chimeric kinase constructs, mutagenesis, co-immunoprecipitation

    PMID:16611982

    Open questions at the time
    • A comprehensive quantitative map of CDC37 affinity across the kinome was lacking
  13. 2007 High

    Kinome-wide analysis in yeast showing that ~78% of kinases depend on Cdc37 for stability established CDC37 as a global kinase quality-control factor, not limited to a handful of oncogenic clients.

    Evidence Systematic analysis of ~65 yeast kinases in cdc37 mutant strains with pulse-chase labeling

    PMID:17242065

    Open questions at the time
    • Whether the same breadth of dependence exists in the mammalian kinome was not tested systematically
  14. 2008 High

    Discovery that PP5/Ppt1 specifically dephosphorylates pSer13-CDC37 within assembled HSP90 complexes (but not free CDC37) completed the CK2–PP5 phosphoregulatory cycle and explained how client release is coupled to dephosphorylation.

    Evidence Phosphatase assays with purified proteins, in vivo phosphorylation analysis in yeast and human cells, genetic studies

    PMID:18922470

    Open questions at the time
    • Temporal order of pSer13 dephosphorylation relative to kinase refolding events was not resolved
    • Whether additional phosphorylation sites on CDC37 contribute remains unclear
  15. 2008 High

    Structural determination of the CDC37 middle domain and its NMR-defined interface with the HSP90 N-domain identified Leu-205 as critical for complex formation, complementing the earlier crystal structure.

    Evidence X-ray crystallography (1.88 Å) and heteronuclear NMR of CDC37 middle domain–HSP90 N-domain complex, mutagenesis

    PMID:19073599

    Open questions at the time
    • How N-terminal and C-terminal domains of CDC37 coordinate during the chaperone cycle was not captured
  16. 2012 High

    Mapping tyrosine phosphorylation events (Y4, Y298 on CDC37; Y197, Y313, Y627 on HSP90) that sequentially disrupt client–CDC37 and CDC37–HSP90 interactions provided a directional model for the chaperone cycle driven by kinase-mediated phosphorylation.

    Evidence Site-directed mutagenesis, phospho-specific antibodies, co-immunoprecipitation, ATPase assays

    PMID:22727666

    Open questions at the time
    • The kinase(s) responsible for each tyrosine phosphorylation event in vivo were not fully identified
    • Temporal ordering of phosphorylation events in living cells was not established
  17. 2013 High

    Demonstrating that CDC37 directly antagonizes ATP binding to client kinases—and that ATP-competitive kinase inhibitors reciprocally displace CDC37—revealed a pharmacologically exploitable competition between drug binding and chaperone association.

    Evidence In vitro ATP-competition binding assays, co-immunoprecipitation in cancer cells treated with vemurafenib/lapatinib

    PMID:23502424

    Open questions at the time
    • Whether this competition affects all CDC37 clients equally was not tested
    • Structural basis for the mutual exclusivity of ATP and CDC37 at atomic resolution was not shown
  18. 2015 High

    Identifying RIP3 as a CDC37–HSP90 client required for necroptosis extended CDC37's functional reach to programmed necrosis, showing it is necessary for RIP3 activation and necroptotic signaling.

    Evidence CDC37 siRNA knockdown blocks necroptosis; co-immunoprecipitation of RIP3–CDC37–HSP90; HSP90 inhibitor treatment

    PMID:25852146

    Open questions at the time
    • Whether CDC37 regulates RIP3 co-translationally or post-translationally was not distinguished
  19. 2016 High

    Near-atomic cryo-EM structure of the HSP90–CDC37–CDK4 complex revealed that CDC37 holds CDK4 with its N- and C-lobes completely separated and the β4–β5 sheet unfolded, resolving how the cochaperone traps kinase clients in a partially unfolded state for chaperone-assisted maturation.

    Evidence Cryo-electron microscopy at 3.9 Å resolution

    PMID:27339980

    Open questions at the time
    • Whether all kinase clients are unfolded to the same extent was unknown
    • How the kinase refolds upon release was not captured
  20. 2016 High

    NMR and HDX experiments showing that CDC37 acts as a conformational scanning factor—locally unfolding client kinases to create high-affinity metastable states while nonclients resist unfolding and dissociate—provided a kinetic discrimination mechanism for client selectivity.

    Evidence NMR spectroscopy, hydrogen-deuterium exchange mass spectrometry, mutagenesis, binding assays

    PMID:27105117

    Open questions at the time
    • The energetic threshold separating clients from nonclients was not quantified
    • Whether post-translational modifications on kinases modulate this discrimination was not tested
  21. 2022 High

    Cryo-EM structures of full-length RAF1–HSP90–CDC37 and BRAFV600E–HSP90–CDC37 complexes, together with phosphoproteomics of PP5 activity, showed how oncogenic mutations favor chaperone association and revealed that PP5 performs comprehensive 'factory-reset' dephosphorylation of client kinases prior to release.

    Evidence Cryo-EM of full-length complexes, phosphoproteomics (LC-MS/MS), PP5 enzymatic assays, mutagenesis

    PMID:36055235 PMID:36446791

    Open questions at the time
    • How the refolded kinase exits the complex and acquires activity remains structurally unresolved
    • Whether PP5-mediated reset applies uniformly across the kinome is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key outstanding questions include: the structural basis for how kinase clients refold and exit the HSP90–CDC37 complex; a systematic quantitative map of CDC37 affinity across the full human kinome; the identity and regulation of tyrosine kinases that phosphorylate CDC37 Y4/Y298 in vivo; and whether CDC37's reported non-kinase clients (androgen receptor, tau) share a structural recognition mechanism with kinase clients.
  • No structural snapshot of the kinase-release step exists
  • Systematic quantitative kinome-wide CDC37 affinity measurements are lacking
  • Non-kinase client recognition mechanism is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0044183 protein folding chaperone 2
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1640170 Cell Cycle 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
AKT1BRAFCDK4CHUKHSP90AA1PPP5CRAF1RIPK3
Complex memberships
HSP90–CDC37 cochaperone complexHSP90–CDC37–kinase ternary complexIKK–HSP90–CDC37 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Mammalian p50Cdc37 was identified as a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4; both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Pharmacological inactivation of Cdc37/Hsp90 decreases the half-life of newly synthesized Cdk4. Co-immunoprecipitation, insect cell reconstitution, pharmacological inhibition (geldanamycin) Genes & development High 8666233
1996 Mammalian CDC37 physically interacts with CDK4 (and CDK6) but not with Cdc2, Cdk2, Cdk3, or Cdk5, suggesting a specific role in CDK4 regulation. CDC37 competes with p16 for binding to CDK4. Yeast two-hybrid, co-immunoprecipitation, in vitro binding The Journal of biological chemistry High 8703009
1995 In yeast, Cdc37 is required for the association of Cdc28 (CDK1) with G1 cyclin Cln2 and mitotic cyclin Clb2; the cdc37-1 mutant shows decreased Cdc28 kinase activity and impaired cyclin binding. Temperature-sensitive yeast mutant analysis, co-immunoprecipitation, kinase activity assays Proceedings of the National Academy of Sciences of the United States of America High 7753858
1997 Cdc37 is itself a molecular chaperone (independent of Hsp90) capable of maintaining denatured beta-galactosidase in an activation-competent state and stabilizing casein kinase II in vitro. In vivo, Cdc37 overexpression can compensate for decreased Hsp90 function for v-Src kinase but not glucocorticoid receptor. In vitro chaperone assay (beta-gal refolding), in vivo complementation, kinase stability assays Genes & development High 9242486
1999 p50(Cdc37) is the primary determinant of Hsp90 recruitment to Raf-1. A Cdc37 mutant unable to recruit Hsp90 into the Raf-1 complex inhibited Raf-1 and MAPK activation by growth factors, demonstrating that formation of a ternary Raf-1–p50(Cdc37)–Hsp90 complex is required for Raf-1 kinase activity. Baculovirus co-expression in Sf9 cells, dominant-negative Cdc37 overexpression, kinase activity assays, co-immunoprecipitation Molecular and cellular biology High 10022854
2002 Intracellular Akt forms a complex with Hsp90 and Cdc37 in which Akt kinase is active and regulated by PI3K. Functional Hsp90 is required for Akt stability; Hsp90 inhibition causes ubiquitination of Akt and proteasomal degradation, shortening Akt half-life from 36 to 12 h. Co-immunoprecipitation, Hsp90 inhibitor treatment, ubiquitination assay, half-life measurement The Journal of biological chemistry High 12176997
2002 Cdc37 and Hsp90 are components of the IKK complex (~900 kDa). Cdc37 directly binds both Hsp90 and the kinase domain of IKKα/IKKβ. Geldanamycin disrupts heterocomplex formation and prevents TNF-induced IKK activation and TNF-R1 recruitment. Co-immunoprecipitation, size-exclusion chromatography, geldanamycin treatment, NF-κB activation assay Molecular cell High 11864612
2002 Cdc37p/p50(cdc37) suppresses the ATPase activity of Hsp90 (similar to Sti1/Hop), binds Hsp90 as a dimer, and forms a stable complex with geldanamycin-bound Hsp90, indicating it may be sequestered in geldanamycin-inhibited Hsp90 complexes in vivo. ATPase activity assay, analytical ultracentrifugation, geldanamycin competition assay The Journal of biological chemistry High 11916974
2003 Mammalian Cdc37 is phosphorylated at Ser13 by casein kinase II in situ and in cultured cells. Mutation of Ser13 (to Ala or Glu) compromises Cdc37 recruitment to Hsp90-kinase complexes and alters Cdc37 modulation of the Hsp90 ATP-driven conformational cycle. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, phosphorylation analysis The Journal of biological chemistry High 12930845
2004 Crystal structure of the Hsp90-p50(cdc37) core complex was determined. Dimeric p50(cdc37) binds to surfaces of the Hsp90 N-domain involved in ATP-dependent N-terminal dimerization, fixes the lid segment in an open conformation, inserts an arginine side chain into the ATP binding pocket to disable catalysis, and prevents trans-activating interaction of the N domains. X-ray crystallography, ATPase activity assay, mutagenesis Cell High 14718169
2004 CK2 phosphorylates Cdc37 at Ser13 in vitro and in vivo. This phosphorylation is essential for optimal binding of Cdc37 to multiple client kinases (Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, MRK) and for recruitment of Hsp90 to kinase-Cdc37 complexes. CK2 inhibition reduces Cdc37 phosphorylation and decreases levels of Cdc37 target kinases. In vitro kinase assay, mutagenesis, co-immunoprecipitation, CK2 inhibitor treatment, western blot Molecular and cellular biology High 15082798
2004 Cdc37's N-terminal domain interacts with immature kinase clients (HRI eIF2α kinase) independently of Hsp90, while the C-terminal domain binds Hsp90. A C-terminal truncation mutant of p50(cdc37) inhibited HRI activation and prevented Hsp90 binding to HRI. Domain mapping with truncation mutants, co-immunoprecipitation, geldanamycin treatment, reticulocyte lysate assay The Journal of biological chemistry Medium 11036079
2004 Cdc37 binds to the N-terminal lobe of Cdk4, requiring residues within the Gly-X-Gly-X-X-Gly ATP-binding motif (Gly-15 and Gly-18). The G-box motif is also required for Cdc37 binding to Raf1. In vitro binding assay, site-directed mutagenesis, cell-based co-immunoprecipitation The Journal of biological chemistry High 14701845
2006 The stoichiometry and 3D structure of the Hsp90-Cdc37-Cdk4 ternary complex was determined by single-particle electron microscopy, identifying locations of Cdc37 and Cdk4 relative to Hsp90 and suggesting coupling of kinase conformational changes to the Hsp90 ATPase cycle. Single-particle electron microscopy, analytical ultracentrifugation, mass spectrometry Molecular cell High 16949366
2006 Cdc37 interacts with the glycine-rich loop (GXFG motif) of the N-lobe of protein kinase clients (including Raf-1 and others). The C-terminal portion of kinases determines differential affinity for Cdc37 (e.g., Cdk4 vs Cdk2). An unphosphorylated activation segment T-loop in a nonclient kinase allows Cdc37 interaction. Phage display, LC-MS/MS, mutagenesis, chimeric kinase constructs, co-immunoprecipitation Molecular and cellular biology High 16611982
2007 In Drosophila, loss of Cdc37 leads to mitotic and meiotic defects phenocopying Aurora B inactivation. Aurora B physically interacts with and requires the Cdc37/Hsp90 complex for its stability, establishing Cdc37/Hsp90 as a regulator of Aurora B in chromosome segregation and cytokinesis. Drosophila genetics (loss-of-function), co-immunoprecipitation, Aurora B activity assay The EMBO journal High 12374737
2008 Cdc37 requires phosphorylation at Ser13 for function in Hsp90-kinase complexes. PP5/Ppt1 phosphatase associates with Hsp90 complexes and specifically dephosphorylates pSer13-Cdc37 within the ternary Hsp90-Cdc37-kinase complex but not isolated Cdc37, revealing a cyclic regulatory mechanism for kinase client activation. Phosphatase assay, co-immunoprecipitation, in vivo phosphorylation analysis, yeast genetic studies Molecular cell High 18922470
2008 Hsp90 and Cdc37 bind the kinase domain of PKC isozymes via a PXXP motif in the C-terminal tail, with Hsp90-binding determinants in regions surrounding the PXXP segment clamped by a conserved Tyr in the αE-helix. This interaction is required for processing phosphorylation of conventional/novel (but not atypical) PKC isozymes. Co-immunoprecipitation, mutagenesis (Pro-to-Ala), peptide array overlay, Hsp90 inhibitor treatment The Journal of biological chemistry High 19091746
2008 Cdc37 recruits Hsp90 to the IKK complex preferentially via IKKα. Cdc37 is essential for the maturation of de novo synthesized IKKs into enzymatically competent kinases, and mature, T-loop-phosphorylated IKKs further require Hsp90-Cdc37 to reach an activated signaling state. siRNA knockdown, co-immunoprecipitation, IKK kinase activity assay, pulse-chase analysis The Journal of biological chemistry High 17728246
2011 The Hsp90-Cdc37 chaperone complex stabilizes and activates Ulk1 kinase; Ulk1 then phosphorylates and releases Atg13, which is recruited to damaged mitochondria for mitophagy. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. Co-immunoprecipitation, Hsp90/Cdc37 inhibition, phosphorylation assays, mitophagy assays, siRNA Molecular cell High 21855797
2012 Tyrosine phosphorylation of p50(Cdc37) at Y4 and Y298 disrupts client-Cdc37 association, while Hsp90 phosphorylation at Y197 dissociates Cdc37 from Hsp90, providing directionality to the chaperone cycle. Hsp90-Y313 phosphorylation then promotes AHA1 recruitment, and Y627 phosphorylation induces client/cochaperone dissociation. Mutagenesis, co-immunoprecipitation, phosphorylation-specific antibodies, ATPase assay Molecular cell High 22727666
2013 Cdc37 directly antagonizes ATP binding to client kinases, and ATP-competitive kinase inhibitors (vemurafenib, lapatinib) antagonize Cdc37 binding to protein kinases, depriving oncogenic kinases (B-Raf, ErbB2) of access to the Hsp90-Cdc37 complex and leading to their degradation. In vitro binding assay, ATP competition assay, co-immunoprecipitation in cancer cells, western blot for kinase levels Nature chemical biology High 23502424
2015 RIP3 activation during necroptosis requires the HSP90-CDC37 cochaperone complex, which physically associates with RIP3. CDC37 knockdown prevents cells from responding to necroptosis stimuli, and HSP90 inhibitors block necroptosis by preventing RIP3 activation. siRNA knockdown, co-immunoprecipitation, HSP90 inhibitor treatment, necroptosis cell death assay Proceedings of the National Academy of Sciences of the United States of America High 25852146
2016 Cryo-EM structure of the Hsp90-Cdc37-Cdk4 complex at 3.9 Å reveals that Cdk4 is trapped in an unfolded state with its two lobes completely separated and the β4-β5 sheet unfolded. Cdc37 mimics part of the kinase N-lobe and wedges between the two lobes, while Hsp90 clamps around the unfolded β5 strand. Single-particle cryo-electron microscopy at 3.9 Å resolution Science (New York, N.Y.) High 27339980
2016 Cdc37 acts as a general kinase scanning factor that recognizes conformational stability determinants in both client and nonclient kinases. Cdc37 locally unfolds client kinases, creating a metastable state with high affinity for Cdc37 and stable multidomain cochaperone association. Nonclients do not undergo this conformational change and dissociate. NMR spectroscopy, hydrogen-deuterium exchange, binding assays, mutagenesis Molecular cell High 27105117
2008 The crystal structure of the 16-kDa middle domain of human Cdc37 was determined at 1.88 Å, and NMR revealed the structure of this domain in complex with the N-terminal domain of human Hsp90. Leu-205 of Cdc37 was identified as a key residue for Hsp90 complex formation. X-ray crystallography, heteronuclear NMR spectroscopy, mutagenesis The Journal of biological chemistry High 19073599
2010 Hsp90-Cdc37 chaperone complex directly interacts with p38α via Cdc37 and suppresses noncanonical p38 autophosphorylation in cardiomyocytes. Cdc37 expression is sufficient and necessary to suppress noncanonical p38 activation at basal state or under TAB1 induction, but does not affect canonical MKK3-mediated p38 activation. Proteomics (mass spectrometry), co-immunoprecipitation, Cdc37 overexpression/knockdown, p38 autophosphorylation assay Circulation research High 20299663
2000 In budding yeast, Cdc37 promotes the stability of both Cdc28 and Cak1 protein kinases. Pulse-chase analysis indicates that Cdc28 and Cak1 are destabilized when Cdc37 function is absent during but not after translation, suggesting a co-translational role. Pulse-chase labeling, temperature-sensitive mutant analysis, co-expression in insect cells Molecular and cellular biology High 10629030
2007 Cdc37 has distinct roles in protein kinase quality control: it protects nascent kinase chains from rapid degradation co-translationally and promotes posttranslational maturation with Hsp90. Analysis of ~50% of the yeast kinome showed 51/65 kinases had decreased abundance in cdc37 mutant cells. Yeast kinome-wide analysis, pulse-chase labeling, genetic (cdc37 mutant strain), protein abundance measurement The Journal of cell biology High 17242065
2002 p50(CDC37) directly binds the reverse transcriptase (RT) of duck hepatitis B virus independently of Hsp90, via interaction with the RT kinase-like domain. p50deltaC (unable to bind Hsp90) still interacts with RT but inhibits protein-primed reverse transcription in vitro and viral replication in cells, demonstrating a functional role as a cellular cofactor for hepadnavirus RT. Co-immunoprecipitation, GST pull-down, in vitro reverse transcription assay, transfection/viral replication assay The Journal of biological chemistry Medium 11986322
2003 LKB1 (Peutz-Jeghers kinase) is associated with Hsp90 and Cdc37 via its kinase domain. Hsp90 inhibitors cause proteasomal degradation of LKB1. A sporadic cancer point mutation in LKB1 weakens interaction with both Hsp90 and Cdc37, enhancing its sensitivity to destabilization. Co-immunoprecipitation, Hsp90 inhibitor treatment, ubiquitination assay, proteasome inhibitor The Biochemical journal High 12489981
2005 JAK1 interacts with Hsp90 and CDC37 in cells; both interactions are destabilized by Hsp90 inhibitors, leading to JAK1/2 proteasomal degradation and consequent blockade of interferon-induced STAT1 phosphorylation and gene expression. siRNA, chemical inhibitors, co-immunoprecipitation, STAT1 phosphorylation assay The Journal of biological chemistry Medium 16280321
2011 Cdc37 co-chaperone directly stabilizes tau protein and physically interacts with tau from human brain. Cdc37 suppression destabilizes tau and alters its phosphorylation profile by reducing stability of specific tau kinases (Cdk5 and Akt) but not others (GSK3β, Mark2). Cdc37 overexpression prevented Hsp90-inhibitor-induced tau clearance. Co-immunoprecipitation (including from human brain), siRNA/overexpression, tau stability assay, kinase activity analysis The Journal of biological chemistry Medium 21367866
2011 Cdc37 directly interacts with IRE1α through a conserved cytosolic motif. Cdc37 knockdown or disruption of Cdc37-IRE1α interaction significantly increased basal IRE1α activity (autophosphorylation), and impaired insulin synthesis and secretion in INS-1 cells. Co-immunoprecipitation, siRNA knockdown, IRE1α activity assay, insulin secretion assay The Journal of biological chemistry Medium 22199355
2017 Differential regulation of CDK4 vs CDK6 by the Cdc37-Hsp90 system: Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and INK CDK inhibitors, whereas CDK4 is more readily released to INKs. CIP/KIP inhibitors cooperate with D-type cyclins to generate CDK4/6-containing ternary complexes resistant to displacement by Cdc37. Co-immunoprecipitation, in vitro binding competition assays, pull-down with purified proteins Cell reports Medium 29091774
2022 Cryo-EM structure of the full-length RAF1-HSP90-CDC37 complex reveals RAF1 with an unfolded N-lobe separated from its C-lobe; CDC37 wraps around HSP90 and contacts both RAF1 lobes. The structure shows how CDC37 discriminates between RAF family members and how folded RAF1 assembles with 14-3-3 dimers for activation. Cryo-electron microscopy (full-length complex), structural analysis, mutagenesis Molecular cell High 36055235
2022 Cryo-EM structure of HSP90-CDC37-BRAFV600E reveals how the V600E mutation favors BRAF association with HSP90-CDC37. PP5 phosphatase is recruited to HSP90 complexes and comprehensively dephosphorylates client proteins including BRAFV600E and CRAF, performing a 'factory reset' prior to client release. Cryo-electron microscopy, phosphoproteomics (LC-MS/MS), PP5 activity assay Nature communications High 36446791
2009 Cdc37 binds to ADP-bound/nucleotide-free Hsp90 but not ATP-bound Hsp90. Celastrol disrupts Hsp90-Cdc37 complex formation and inhibits Hsp90 ATPase activity by binding to the Hsp90 C-terminal domain. GST pull-down, ELISA, ATPase assay, proteolytic fingerprinting The Journal of biological chemistry Medium 19858214
2000 Human androgen receptor (AR) binds to Cdc37 via its ligand-binding domain in a manner partially dependent on Hsp90 and hormone; Cdc37 does not interact with glucocorticoid receptor. Dominant-negative Cdc37 downregulates full-length AR but not AR lacking the ligand-binding domain, demonstrating Cdc37 client activity extends beyond kinases. Co-immunoprecipitation, rabbit reticulocyte lysate binding, dominant-negative overexpression, western blot The Journal of biological chemistry Medium 11085988
2007 Pink1 (PARK6 Parkinson's kinase) is a Cdc37/Hsp90 client kinase. Mass spectrometry of immunoisolated Pink1 complexes identified Cdc37/Hsp90. The chaperone system influences Pink1 subcellular distribution and the 66/55 kDa protein ratio. A pathogenic Pink1 L347P mutation decreases Hsp90/Cdc37 binding, and the L347P protein is rapidly degraded via the proteasome. Mass spectrometry (immunoisolation), co-immunoprecipitation, Hsp90 inhibitor treatment, half-life measurement Human molecular genetics High 18003639 18359116
2015 Cell-surface Cdc37 is present on breast cancer cells and interacts with surface HSP90, HER2, and EGFR, participating in cancer cell motility. Functional inhibition of surface HSP90 disrupts both the surface Cdc37/HSP90 complex and Cdc37/ErbB receptor complexes. Cell-impermeable antibody treatment, co-immunoprecipitation (surface proteins), cell migration/invasion assay PloS one Low 22912728

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. The Journal of biological chemistry 557 12176997
1996 Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes & development 442 8666233
2002 TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Molecular cell 326 11864612
2016 Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science (New York, N.Y.) 323 27339980
2008 A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Molecular cancer therapeutics 311 18202019
2004 The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell 279 14718169
2006 Structure of an Hsp90-Cdc37-Cdk4 complex. Molecular cell 247 16949366
1999 p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Molecular and cellular biology 233 10022854
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