Structure and Mechanism of the Hsp90 Molecular Chaperone Machinery

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell. Biochemical and structural analysis of Hsp90 has revealed a complex mechanism of ATPase-coupled conformational changes and interactions with cochaperone proteins, which facilitate activation of Hsp90's diverse "clientele." Despite recent progress, key aspects of the ATPase-coupled mechanism of Hsp90 remain controversial, and the nature of the changes, engendered by Hsp90 in client proteins, is largely unknown. Here, we discuss present knowledge of Hsp90 structure and function gleaned from crystallographic studies of individual domains and recent progress in obtaining a structure for the ATP-bound conformation of the intact dimeric chaperone. Additionally, we describe the roles of the plethora of cochaperones with which Hsp90 cooperates and growing insights into their biochemical mechanisms, which come from crystal structures of Hsp90 cochaperone complexes.

Firefly luciferase mutants as sensors of proteome stress

“…The middle domain is followed by a carboxy-terminal domain (CTD) which mediates dimerization and is less conserved in sequence (Harris et al, 2004;Minami et al, 1994). The five C-terminal residues (MEEVD motif) form a highly conserved TPR domain binding site that allows Hsp90 to interact with a number of co-chaperones containing TPR domains (Pearl and Prodromou, 2006;Young et al, 1998).…”

Hsp90—From signal transduction to cell transformation

“…Instead, it serves at the core of various multiprotein complexes that incorporate other chaperones, such as Hsp70, and an assortment of co-chaperones [5,27]. The broadest class of Hsp90 co-chaperones are those containing one or more tetratricopeptide repeat (TPR) motifs that interact with the Cterminal domain of Hsp90 [28].…”

“…Hsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7].…”

“…Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8].…”

“…These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. …”