Hsp90 and client protein maturation

Abstract

Heat-shock protein 90 (Hsp90) is a molecular chaperone that assists in the maturation of a limited set of substrate proteins that are collectively referred to as clients. The majority of identified Hsp90 clients are involved in signal transduction, including many steroid hormone receptors and kinases. A handful of Hsp90 clients can be classified as nonsignal transduction proteins, including telomerase, cystic fibrosis transmembrane conductance regulator, and antigenic peptides destined for major histocompatibility complex. Because Hsp90 clients are causative agents in cancer and cystic fibrosis, research on Hsp90 has intensified in recent years. We review the historical path of Hsp90 research within each class of client (kinase, hormone receptor, and nonsignal transduction clients) and highlight current areas of active investigation.

Figure 8.1. Model of the ATPase driven conformational cycle of Hsp90 that leads to client maturation

In addition to client and ATP, numerous co-chaperones bind to Hsp90 and influence its chaperone activity. Many of these Hsp90 binding interactions are inter-dependent. The nucleotide-bound state of Hsp90 influences the binding of both co-chaperones and clients. Understanding how the inter-dependent and often transient binding of co-chaperones and nucleotide lead to client maturation is an active area of investigation.