Molecular Mechanism of Protein Kinase Recognition and Sorting by the Hsp90 Kinome-Specific Cochaperone Cdc37.
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.
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Dimitra
D
Keramisanou
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Adam
A
Aboalroub
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Ziming
Z
Zhang
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Wenjun
W
Liu
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Devon
D
Marshall
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Andrea
A
Diviney
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
Randy W
RW
Larsen
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Ralf
R
Landgraf
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA. Electronic address: igelis@usf.edu.
Ioannis
I
Gelis
D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018833:Chaperonins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011487:Protein Conformation; D055550:Protein Stability; D058767:Protein Unfolding; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013696:Temperature; D014162:Transfection
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018833:Chaperonins