Structure, function, and mechanism of the Hsp90 molecular chaperone

Abstract

This chapter discusses the current knowledge of the structure and biochemistry of the Hsp90 family of molecular chaperones, with particular attention to the emerging understanding of the role of its ATPase activity and the opportunities this presents for and-chaperone drug development. It focuses on various co-chaperones that are known to interact with Hsp90, examining their roles in Hsp90 function as well as the complicated picture of dynamic and varied Hsp90/co-chaperone complexes that is emerging. In addition, the chapter also mentions the current understanding of the interaction of Hsp90 with its client proteins, the possible origins of client-protein specificity, and the change of state in the client proteins that is achieved by their involvement in the ATP-dependent chaperone cycle of Hsp90. In the eukaryotic Hsp90s, the N-terminal nucleotide-binding domain is connected to the remainder of the protein by a highly charged and proteolytically sensitive segment that is variable both in length and composition between different species and between different isoforms in the same species. However, many of the key phenomena associated with this system remain obscure. Most notably, the roles of the expanding set of co-chaperones and the nature of the interaction between Hsp90 and the client proteins are still very poorly understood.