Hsp90: a specialized but essential protein-folding tool

Abstract

Hsp90 is unique among molecular chaperones. The majority of its known substrates are signal transduction proteins, and recent work indicates that it uses a novel protein-folding strategy.

Figure 1.

Structural basis for the interaction of Hsp90 with nucleotides, ansamycin drugs, and TPR domain cochaperones. (A) Domain organization of Hsp90. Amino acid numbers of domain boundaries for human Hsp90α are marked. See text for references. (B) Crystal structures of the Hsp90 NH₂-terminal domain complexed with ADP and with the ansamycin drug GA (Prodromou et al., 1997; Stebbins et al., 1997). The proposed lid sequence over the nucleotide-binding pocket is indicated. (C) Crystal structures of the Hsp70-binding NH₂-terminal TPR domain of Hop complexed with the Hsp70 COOH-terminal peptide GPTIEEVD (left) and the Hsp90-binding central TPR domain of Hop complexed with the Hsp90 COOH-terminal peptide MEEVD (right). Structures in the bottom panel are rotated 90°C from the top panel. The peptides are oriented with the COOH-terminal carboxyl groups at the bottom of the figure (top) and towards the viewer (bottom) (Scheufler et al., 2000).

Figure 2.

The substrate-binding ATPase cycle of Hsp90 (Chadli et al., 2000; Prodromou et al., 2000; Young and Hartl, 2000). (1) Polypeptide substrate may be transferred from Hsc70 to the nucleotide-free state of Hsp90 induced by Hop. (2) Hsp90 in the open nucleotide-free state can bind substrate polypeptide. (3) ATP binding induces dimerization of the NH₂-terminal domains of Hsp90 (circles) and permits p23 binding; substrate is bound by Hsp90 clamp. (4) Hydrolysis of bound ATP releases substrate by opening clamp or by inducing some other conformational change.

Figure 3.

Different modes of Hsp90 action in signaling pathways. (A) Inactive steroid hormone receptors are folded by the Hsp90 machinery. Folded receptors either are stabilized and activated by hormone binding or remain unstable and are rebound by chaperones (Smith, 1993; Pratt and Toft, 1997). (B) Ecdysone receptor with its partner USP can bind hormone but requires folding by the Hsp90 machinery to become active for DNA binding (Arbeitman and Hogness, 2000). (C) Monomeric HSF1 is sequestered by Hsp90. Under stress conditions, misfolded proteins compete for Hsp90, and HSF1 is displaced from Hsp90 and can form the active trimer (Zou et al., 1998).