Hsp90 and co-chaperones twist the functions of diverse client proteins

Abstract

Hsp90 molecular chaperones are required for the stability and activity of a diverse range of client proteins that have critical roles in signal transduction, cellular trafficking, chromatin remodeling, cell growth, differentiation, and reproduction. Mammalian cells contain three types of Hsp90s: cytosolic Hsp90, mitochondrial Trap-1, and Grp94 of the endoplasmic reticulum. Each of the Hsp90s, as well as the bacterial homolog, HtpG, hydrolyze ATP and undergo similar conformational changes. Unlike the other forms of Hsp90, cytosolic Hsp90 function is dependent on a battery of co-chaperone proteins that regulate the ATPase activity of Hsp90 or direct Hsp90 to interact with specific client proteins. This review will summarize what is known about Hsp90's ability to mediate the folding and activation of diverse client proteins that contribute to human diseases, such as cancer and fungal and viral infections.

Figure 1. Hsp90 ATPase cycle

In the absence of ATP (A), Hsp90 is dimerized at its C-terminus in the ‘open’ conformation. Upon ATP binding (B), the N-terminal domains undergo subsequent conformational changes that result in closing of a ‘lid’ over the bound nucleotide (C) and formation of a second dimerization interface between the amino-termini (D, the ‘closed’ conformation). Continued rearrangements of the closed conformation allow interaction of the N-terminal and middle domains resulting in the ‘closed and twisted’ conformation which is able to hydrolyze ATP (E). After ATP hydrolysis the lid opens and the N-terminal domains release from one another returning to the open conformation (A). Co-chaperones bind Hsp90 and modulate the ATPase cycle. Hop/Sti1 and Cdc37 inhibit the ATPase activity by keeping the Hsp90 in the open conformation. Aha1 stimulates ATP hydrolysis by promoting formation of the closed conformation, while Sba1 stabilizes the closed and twisted conformation.