THE HSP90 COMPLEX - A SUPER-CHAPERONE MACHINE AS A NOVEL DRUG TARGET

Cells respond to sudden changes in the environmental temperature with increased synthesis of a distinct number of heat shock proteins (Hsps) . Analysis of the function of these proteins in recent years has shown that all the major classes of conserved Hsps are molecular chaperones involved in assisting cellular protein folding anti preventing irreve rsible side-reactions, such as unspecific aggregation. In addition to their function under stress conditions, molecular chaperones also play a critical role under physiological conditions. Hsp90 is one of the m ost abundant chaperones in the cytosol of eukaryotic cells. It is part of the cell's powerful network of chaperones to fight the deleterious consequences of protein unfolding caused by nonphysiological conditio ns. In the absence of stress, however, Hsp90 is an obligate component of fundamental cellular processes such as hormone signaling and cell c ycle control. In this context, several key regulatory proteins, such a s steroid receptors, cell cycle kinases, and p53, have been identified as substrates of Hsp90. Recently, Hsp90 was shown to be the unique ta rget for geldanamycin, a potent new anti-tumor drug that blocks cell p roliferation. Interestingly, under physiological conditions, Hsp90 see ms to perform its chaperone function in a complex with a set of partne r proteins, suggesting that the Hsp90 complex is a multi-chaperone mac hine specialized in guiding the maturation of conformationally labile proteins. The regulation of key signaling molecules of the cell by the Hsp90 machinery is a stimulating new concept emerging from these stud ies, and Hsp90 has become a promising new drug target. (C) 1998 Elsevi er Science Inc.