Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37

Dimitra Keramisanou, Adam Aboalroub, Ziming Zhang, Wenjun Liu, Devon Marshall, Andrea Diviney, Randy W. Larsen, Ralf Landgraf, Ioannis Gelis

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Despite the essential functions of Hsp90, little is known about the mechanism that controls substrate entry into its chaperone cycle. We show that the role of Cdc37 cochaperone reaches beyond that of an adaptor protein and find that it participates in the selective recruitment of only client kinases. Cdc37 recognizes kinase specificity determinants in both clients and nonclients and acts as a general kinase scanning factor. Kinase sorting within the client-to-nonclient continuum relies on the ability of Cdc37 to challenge the conformational stability of clients by locally unfolding them. This metastable conformational state has high affinity for Cdc37 and forms stable complexes through a multidomain cochaperone interface. The interaction with nonclients 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 stable cochaperone association. Cdc37 cochaperone participates in the chaperoning of protein kinases by the Hsp90 machinery. Keramisanou et al. reveal that the cochaperone provides broad kinase specificity and client selectivity. By challenging their conformational stability, Cdc37 senses the thermal stability of client kinases and actively participates in kinase quality control.

Original languageEnglish (US)
Pages (from-to)260-271
Number of pages12
JournalMolecular Cell
Volume62
Issue number2
DOIs
StatePublished - Apr 21 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Keramisanou, D., Aboalroub, A., Zhang, Z., Liu, W., Marshall, D., Diviney, A., Larsen, R. W., Landgraf, R., & Gelis, I. (2016). Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37. Molecular Cell, 62(2), 260-271. https://doi.org/10.1016/j.molcel.2016.04.005