Cdc37 and Hsp90 tyrosine phosphorylation modulate the kinase chaperone cycle

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