Proteomics

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Cdc37 and Hsp90 tyrosine phosphorylation modulate the kinase chaperone cycle

ABSTRACT: Cdc37 is a core cochaperone of the Hsp90 machinery. It is involved in an early stage of the chaperone cycle to activate nascent forms of protein kinases as well as to stabilize mature forms of a subset of protein kinases. Overall, the chaperone cycle is quite complex and involves several steps. Progression, through these steps is regulated by the incorporation of several other cochaperones, ATP hydrolysis and posttranslational modifications on both Cdc37 and Hsp90. We show that phosphorylation of Cdc37 at Y298 by Yes kinase results in partial unfolding of its C-terminal domain, without affecting its ability to form binary or ternary complexes with kinases and Hsp90. Unfolding, unmasks a phosphopeptide sequence that exhibits high affinity for SH2 domains of non-receptor tyrosine kinases (nRTKs), resulting in their recruitment in the chaperone complex. In turn, the high local concentration of nRTKs potentiates Hsp90 phosphorylation at Y197, which results in dissociation of this early kinase-recruitment complex

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Dale Chaput  

LAB HEAD: Dr. Ioannis Gelis

PROVIDER: PXD008375 | Pride | 2018-01-22

REPOSITORIES: Pride

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20170404_set1_Cdc37-1.raw Raw
20170404_set1_Cdc37-2.raw Raw
20170404_set1_Cdc37-3.raw Raw
20170404_set1_Cdc37-8.raw Raw
20170404_set1_Hsp90-3.raw Raw
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Publications

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

Bachman Ashleigh B AB   Keramisanou Dimitra D   Xu Wanping W   Beebe Kristin K   Moses Michael A MA   Vasantha Kumar M V MV   Gray Geoffrey G   Noor Radwan Ebna RE   van der Vaart Arjan A   Neckers Len L   Gelis Ioannis I  

Nature communications 20180117 1

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 recr  ...[more]

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