Protein Kinase Recognition and Sorting by the HSP90 Kinome-Specific Cochaperone CDC37

Abstract

The Hsp90 chaperone machinery is a ubiquitous mediator of protein homeostasis and activity. Despite its essential roles, little is known about the molecular mechanism that controls substrate entry into its chaperone cycle. Here we show that the functional role of the kinome-specific cochaperone, Cdc37, reaches beyond that of an adapter protein and find that it actively participates in the selective recruitment of only client kinases. The cochaperone recognizes kinase specificity determinants in both clients and non-clients and thus it acts as a general kinase scanning-factor. Kinase sorting within the client to non-client continuum relies on the ability of Cdc37 to challenge the conformational stability of client kinases by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through an extended, multi-domain cochaperone interface. On the other hand, the interaction with non-clients is not accompanied by conformational changes of the substrate and results in substrate dissociation. Collectively, Cdc37 performs a quality control of protein kinases, where induced conformational instability acts as a “flag” for Hsp90 dependence and thus stable cochaperone association.