Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation

Ashleigh B. Bachman, Dimitra Keramisanou, Wanping Xu, Kristin Beebe, Michael A. Moses, M. V. Vasantha Kumar, Geoffrey Gray, Radwan Ebna Noor, Arjan van der Vaart, Len Neckers and Ioannis Gelis ()
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Ashleigh B. Bachman: University of South Florida
Dimitra Keramisanou: University of South Florida
Wanping Xu: National Cancer Institute
Kristin Beebe: National Cancer Institute
Michael A. Moses: National Cancer Institute
M. V. Vasantha Kumar: University of South Florida
Geoffrey Gray: University of South Florida
Radwan Ebna Noor: University of South Florida
Arjan van der Vaart: University of South Florida
Len Neckers: National Cancer Institute
Ioannis Gelis: University of South Florida

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract During the Hsp90-mediated chaperoning of protein kinases, the core components of the machinery, Hsp90 and the cochaperone Cdc37, recycle between different phosphorylation states that regulate progression of the chaperone cycle. We show that Cdc37 phosphorylation at Y298 results in partial unfolding of the C-terminal domain and the population of folding intermediates. Unfolding facilitates Hsp90 phosphorylation at Y197 by unmasking a phosphopeptide sequence, which serves as a docking site to recruit non-receptor tyrosine kinases to the chaperone complex via their SH2 domains. In turn, Hsp90 phosphorylation at Y197 specifically regulates its interaction with Cdc37 and thus affects the chaperoning of only protein kinase clients. In summary, we find that by providing client class specificity, Hsp90 cochaperones such as Cdc37 do not merely assist in client recruitment but also shape the post-translational modification landscape of Hsp90 in a client class-specific manner.

Date: 2018
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DOI: 10.1038/s41467-017-02711-w

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