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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.
Highlights
During the Heat shock protein 90 (Hsp90)-mediated chaperoning of protein kinases, the core components of the machinery, Hsp[90] and the cochaperone Cdc[37], recycle between different phosphorylation states that regulate progression of the chaperone cycle
In the NMR structure of C-Cdc3740, the –OH group of Y298 lies within hydrogen bond distance to the carboxylate group of D310 and the carbonyl group of Q306 (Fig. 1a)
In ternary complexes of the doublephosphomimetic mutant Cdc37EE, Hsp90Y197 phosphorylation was compromised and still lower relative to ternary complexes of the wild-type protein (Fig. 5). These results suggest that Yes-mediated Cdc37Y298 phosphorylation uniquely promotes Hsp90Y197 phosphorylation and that the Hsp90Y197dependent assembly and disassembly of the recruitment complex are characterized by a coupled phosphorylation mechanism
Summary
During the Hsp90-mediated chaperoning of protein kinases, the core components of the machinery, Hsp[90] and the cochaperone Cdc[37], recycle between different phosphorylation states that regulate progression of the chaperone cycle. Hsp[90] PTMs occur as molecular events that assist in the timely progression through the chaperone cycle[20] or as a response to stimuli such as DNA damage[21,22] and nitric oxide levels[23] They have diverse functional consequences that range from altered interaction profiles with clients[24], cochaperones[20,25], nucleotides, or small-molecule inhibitors[25], to translocation[26,27], secretion[28], and conformational changes[29,30,31]. Our data reveal a mechanism by which specific Hsp[90] modification patterns may occur through cochaperone-mediated recruitment of the corresponding modifying enzymes
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