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Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.

Cell | Aug 31, 2012

HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.

Pubmed ID: 22939624 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Cell Cycle Proteins | Chaperonins | HSP90 Heat-Shock Proteins | Humans | Luciferases, Renilla | Models, Molecular | Molecular Sequence Data | Protein Interaction Domains and Motifs | Protein Interaction Mapping | Protein Kinases | Protein Stability | Proteome | Receptors, Steroid | Sequence Alignment | Thermodynamics | Transcription Factors | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NIDCR NIH HHS, Id: UL1-DE019585
  • Agency: NIDCR NIH HHS, Id: UL1 DE019585
  • Agency: NIGMS NIH HHS, Id: RL1-GM084437
  • Agency: Howard Hughes Medical Institute, Id: RL1-CA133834
  • Agency: NCI NIH HHS, Id: RL1 GM084437
  • Agency: NIGMS NIH HHS, Id: RL1-HG004671
  • Agency: NHGRI NIH HHS, Id: RL1 HG004671
  • Agency: NHGRI NIH HHS, Id: RL1 CA133834
  • Agency: NCI NIH HHS, Id:

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