Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.

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TitleAtomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.
Publication TypeJournal Article
Year of Publication2016
AuthorsVerba, KA, Wang, RYu-Ruei, Arakawa, A, Liu, Y, Shirouzu, M, Yokoyama, S, Agard, DA
JournalScience
Volume352
Issue6293
Pagination1542-7
Date Published2016 Jun 24
ISSN1095-9203
KeywordsAnimals, Cell Cycle Proteins, Chaperonins, Cyclin-Dependent Kinase 4, Enzyme Stability, HSP90 Heat-Shock Proteins, Humans, Models, Molecular, Multiprotein Complexes, Protein Structure, Secondary, Protein Unfolding, Sf9 Cells
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.

DOI10.1126/science.aaf5023
Alternate JournalScience
PubMed ID27339980
PubMed Central IDPMC5373496
Grant List / / Howard Hughes Medical Institute / United States
P41 GM103310 / GM / NIGMS NIH HHS / United States
U01 GM098254 / GM / NIGMS NIH HHS / United States
9 P41 GM103310 / GM / NIGMS NIH HHS / United States