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Reference: Prodromou C and Pearl LH (2003) Structure and functional relationships of Hsp90. Curr Cancer Drug Targets 3(5):301-23

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Abstract

Understanding the mode of action of Hsp90 requires that molecular detail of its interactions with client proteins and co-chaperones are known. The structure determination of the N-terminal domain of Hsp90/Hsp90beta, proof that it is an ATPase, that this activity is regulated and the identification of co-chaperones that facilitate Hsp90 function were landmarks towards understanding conformational changes in Hsp90 brought about by ATP, co-chaperones and client proteins. Sti1 and Cdc37/p50, which associate with early Hsp90 complexes, were shown to be inhibitors of Hsp90 ATPase activity and therefore promote its 'open' state, whereas Sba1/p23, which associates with mature complexes, inhibits ATPase activity and stabilises the 'closed' state. The isolation and characterisation of Aha1, the only known strong activator of Hsp90 ATPase activity, which promotes the 'closed' state of Hsp90, will also be of major importance in understanding Hsp90 function. The structure determination of the middle region of Hsp90 has shed further light on the complex ATP-cycle of Hsp90, identifying a catalytic loop, with key residues that are essential for ATP hydrolysis. These studies, together with biochemical ones, suggest that ATP hydrolysis, is dependent on a complex rate-limiting step, involving N-terminal dimerization and association of the middle region, and therefore the catalytic loop, of Hsp90 with the N-terminal domains. The structure of the middle region of Hsp90 will also accelerate our understanding of client protein interactions since this region is implicated in their recognition and in particular their active-site openings.

Reference Type
Journal Article | Review | Research Support, Non-U.S. Gov't
Authors
Prodromou C, Pearl LH
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