Abstract
Hsp90 is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp90 client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp90 ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp90 for nucleotide substrates. The ability of yeast Aha-type co-chaperones to act in vivo is ablated when the N terminal NxNNWHW motif is removed. This work suggests that nucleotide exchange during the Hsp90 functional cycle may be more important than rate of catalysis.
Highlights
Hsp[90] is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins
We investigated the importance of the NxNNWHW motif in the biological and biochemical activities of Hch1p and Aha1p
Aha1p and Hch1p share several sequence elements that are important for regulating the ATPase activity of Hsp[90] in vitro as well as Hsp[90] function in vivo[7,13,19,30,44]
Summary
Hsp[90] is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp[90] client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp[90] ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp[90] for nucleotide substrates. Client activation during the Hsp[90] functional cycle is regulated by a cohort of proteins called co-chaperones[3,4,5,6,7,8,9,10,11,12,13]. The cellular activity of Hsp[90] appears to be influenced by the relative expression levels of Aha[1] and other co-chaperones which are normally far less abundant than the chaperone itself[25,26]
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