Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
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Taipale-2012-Quantitative Analysi.pdf
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Author(s)
Taipale, Mikko
Krykbaeva, Irina
Kayatekin, Can
Westover, Kenneth D.
Karras, Georgios I.
Lindquist, Susan
Koeva, Martina I
Date Issued
August 2012
Journal
Cell
Publisher
Elsevier
Citation
Taipale, Mikko, Irina Krykbaeva, Martina Koeva, Can Kayatekin, Kenneth D. Westover, Georgios I. Karras, and Susan Lindquist. “Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition.” Cell 150, no. 5 (August 2012): 987–1001. © 2012 Elsevier Inc.
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Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1016/j.cell.2012.06.047
