Hsp90 recognizes a common surface on client kinases.
Hsp90 is a highly abundant chaperone whose clientele includes hundreds of cellular proteins, many of which are central players in key signal transduction pathways and the majority of which are protein kinases. In light of the variety of Hsp90 clientele, the mechanism of selectivity of the chaperone toward its client proteins is a major open question. Focusing on human kinases, we have demonstrated that the chaperone recognizes a common surface in the amino-terminal lobe of kinases from diverse families, including two newly identified clients, NFkappaB-inducing kinase and death-associated protein kinase, and the oncoprotein HER2/ErbB-2. Surface electrostatics determine the interaction with the Hsp90 chaperone complex such that introduction of a negative charge within this region disrupts recognition. Compiling information on the Hsp90 dependence of 105 protein kinases, including 16 kinases whose relationship to Hsp90 is first examined in this study, reveals that surface features, rather than a contiguous amino acid sequence, define the capacity of the Hsp90 chaperone machine to recognize client kinases. Analyzing Hsp90 regulation of two major signaling cascades, the mitogen-activated protein kinase and phosphatidylinositol 3-kinase, leads us to propose that the selectivity of the chaperone to specific kinases is functional, namely that Hsp90 controls kinases that function as hubs integrating multiple inputs. These lessons bear significance to pharmacological attempts to target the chaperone in human pathologies, such as cancer.
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 97100, Israel.
Ami
A
Citri
Daniel
D
Harari
Galit
G
Shohat
Parameswaran
P
Ramakrishnan
Judith
J
Gan
Sara
S
Lavi
Miriam
M
Eisenstein
Adi
A
Kimchi
David
D
Wallach
Shmuel
S
Pietrokovski
Yosef
Y
Yarden
D000595:Amino Acid Sequence; D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D055672:Static Electricity
D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases