title: Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Mikko
authors.initials: M
authors.lastname: Taipale
authors.forename: Irina
authors.initials: I
authors.lastname: Krykbaeva
authors.forename: Martina
authors.initials: M
authors.lastname: Koeva
authors.forename: Can
authors.initials: C
authors.lastname: Kayatekin
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Karras
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D018833:Chaperonins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D049410:Luciferases, Renilla / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D055550:Protein Stability; D020543:Proteome / Q000032:analysis; D011987:Receptors, Steroid / Q000378:metabolism; D016415:Sequence Alignment; D013816:Thermodynamics; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D020543:Proteome; D011987:Receptors, Steroid; D014157:Transcription Factors; D049410:Luciferases, Renilla; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D018833:Chaperonins