Quantitative analysis of Hsp90-client interactions reveals principles of substrate recognition

Mikko Taipale, Irina Krykbaeva, Martina Koeva, Can Kayatekin, Kenneth D. Westover, Georgios I. Karras, Susan Lindquist

Research output: Contribution to journalArticle

438 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)987-1001
Number of pages15
JournalCell
Volume150
Issue number5
DOIs
StatePublished - Aug 31 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K. D., Karras, G. I., & Lindquist, S. (2012). Quantitative analysis of Hsp90-client interactions reveals principles of substrate recognition. Cell, 150(5), 987-1001. https://doi.org/10.1016/j.cell.2012.06.047