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Biochem. J. (2008) 410 (439–453) (Printed in Great Britain)

Review article

The Hsp90 molecular chaperone: an open and shut case for treatment

Laurence H. PEARL*1, Chrisostomos PRODROMOU* and Paul WORKMAN†

*Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, U.K., and †Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, U.K.

The molecular chaperone Hsp90 (90 kDa heat-shock protein) is a remarkably versatile protein involved in the stress response and in normal homoeostatic control mechanisms. It interacts with ‘client proteins’, including protein kinases, transcription factors and others, and either facilitates their stabilization and activation or directs them for proteasomal degradation. By this means, Hsp90 displays a multifaceted ability to influence signal transduction, chromatin remodelling and epigenetic regulation, development and morphological evolution. Hsp90 operates as a dimer in a conformational cycle driven by ATP binding and hydrolysis at the N-terminus. The cycle is also regulated by a group of co-chaperones and accessory proteins. Here we review the biology of the Hsp90 molecular chaperone, emphasizing recent progress in our understanding of structure–function relationships and the identification of new client proteins. In addition we describe the exciting progress that has been made in the development of Hsp90 inhibitors, which are now showing promise in the clinic for cancer treatment. We also identify the gaps in our current understanding and highlight important topics for future research.

Key words: ATPase inhibitor, cancer therapy, client protein, co-chaperone, protein activation and degradation, ubiquitination.

Abbreviations used: 17-AAG, 17-(allylamino)-17-demethoxygeldanamycin (tanespimycin); 17-DMAG, 17-dimethylaminoethylamino-17-demethoxygeldanamycin; Aha1, activator of Hsp90 ATPase; b-Raf, v-raf murine sarcoma viral oncogene homologue B1; CBF3, centromere-binding factor 3; Cdc37, cell-division cycle 37 homologue; Cdk4, cyclin-dependent kinase 4; CFTR, cystic fibrosis transmembrane conductance regulator; CHIP, C-terminal of Hsp70 interacting protein; Chk1, checkpoint kinase 1; CHORD, cysteine- and histidine-rich domain; Chp-1, CHORD-containing protein 1; CS domain, CHORD–Sgt1 domain; DAPK, death-associated protein kinase; EGFR, epidermal-growth-factor receptor; ErbB2, v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2; GRP94, 94 kDa glucose-regulated protein; HBV, hepatitis B virus; HDAC, histone deacetylase; Hop, heat-shock protein organizing protein; Hsc70, heat-shock 70 kDa cognate protein; HSF1, heat-shock factor 1; Hsp70, 70 kDa heat-shock protein; Hsp90, 90 kDa heat-shock protein; LRR, leucine-rich repeat; N-domains, N-terminal ATP-binding domains; NLR, Nod-like receptor; Nod, nuclear oligomerization domain; p[NH]ppA, adenosine 5´-[b,g-imido]triphosphate; PKB, protein kinase B; PRMT, protein-arginine methyltransferase; R protein, resistance protein; Rar1, required for Mla12 resistance; Rvb1p, RuvB-like protein 1; SCF, Skp1–Cullin 1–F-box; SGS, Sgt1-specific; Sgt1, suppressor of G2 allele of Skp1 (S-phase kinase-associated protein 1); Sti1, stress-inducible protein 1 (the yeast homologue of Hop); Tah1p, tetratricopeptide-repeat-containing protein associated with Hsp90; TPR, tetratricopeptide repeat; Trap1, tumour-necrosis-factor-receptor-associated protein 1.

¹To whom correspondence should be addressed (email laurence.pearl@icr.ac.uk).

Received 5 December 2007; accepted 9 January 2008

Published on the Internet 27 February 2008, doi:10.1042/BJ20071640

© The Authors Journal compilation © 2008 Biochemical Society

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