title: Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.
abstract: The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" kinases and the reason why some kinases are addicted to Hsp90 while closely related family members are independent are unknown. Our structural understanding of these interactions is lacking, as no full-length structures of human Hsp90, Cdc37, or either of these proteins with a kinase have been elucidated. Here we report a 3.9 angstrom cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex. Surprisingly, the two lobes of Cdk4 are completely separated with the β4-β5 sheet unfolded. Cdc37 mimics part of the kinase N lobe, stabilizing an open kinase conformation by wedging itself between the two lobes. Finally, Hsp90 clamps around the unfolded kinase β5 strand and interacts with exposed N- and C-lobe interfaces, protecting the kinase in a trapped unfolded state. On the basis of this structure and an extensive amount of previously collected data, we propose unifying conceptual and mechanistic models of chaperone-kinase interactions.
authors.affiliation: Howard Hughes Medical Institute (HHMI) and the Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Kliment A
authors.initials: KA
authors.lastname: Verba
authors.affiliation: Howard Hughes Medical Institute (HHMI) and the Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ray Yu-Ruei
authors.initials: RY
authors.lastname: Wang
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Arakawa
authors.affiliation: Howard Hughes Medical Institute (HHMI) and the Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Howard Hughes Medical Institute (HHMI) and the Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA. agard@msg.ucsf.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Agard
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000648:ultrastructure; D018833:Chaperonins / Q000737:chemistry* / Q000648:ultrastructure; D051358:Cyclin-Dependent Kinase 4 / Q000737:chemistry* / Q000648:ultrastructure; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D061987:Sf9 Cells
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D046912:Multiprotein Complexes; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018833:Chaperonins