Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone that is involved in the activation of disparate client proteins. This implicates Hsp90 in diverse biological processes that require a variety of co-ordinated regulatory mechanisms to control its activity. Perhaps the most important regulator is heat shock factor 1 (HSF1), which is primarily responsible for upregulating Hsp90 by binding heat shock elements (HSEs) within Hsp90 promoters. HSF1 is itself subject to a variety of regulatory processes and can directly respond to stress. HSF1 also interacts with a variety of transcriptional factors that help integrate biological signals, which in turn regulate Hsp90 appropriately. Because of the diverse clientele of Hsp90 a whole variety of co-chaperones also regulate its activity and some are directly responsible for delivery of client protein. Consequently, co-chaperones themselves, like Hsp90, are also subject to regulatory mechanisms such as post translational modification. This review, looks at the many different levels by which Hsp90 activity is ultimately regulated.
Highlights
Heat shock protein 90 (Hsp90) accounts for 1–2 % of the cellular protein and rises to 4–6 % in stressed cells [1,2,3,4]
The cytoplasmic Hsp90 proteins are required for a whole host of biological processes, including adaptation to stress
heat shock factor 1 (HSF1) emerges as a master regulator of the heat-shock response (HSR), helping integrate a variety of cellular signals into Hsp90 transcriptional control
Summary
Hsp (heat-shock protein 90) accounts for 1–2 % of the cellular protein and rises to 4–6 % in stressed cells [1,2,3,4]. Hsp90α and Hsp90β interact with approximately 10 % of the eukaryotic proteome [20], representing ∼2000 proteins [21], of which, to date, ∼725 experimentally determined interactions have been confirmed by direct protein–protein interaction experiments This implicates Hsp in diverse biological processes [3] that necessitate a wide range of mechanisms to regulate its function. ATPase activity of Hsp is achieved when the middle domain catalytic loop of Hsp moves to an open active state [26] (Figure 2) This loop possesses a conserved arginine residue (Arg380 in yeast), which interacts with the γ -phosphate of ATP, and promotes ATP hydrolysis by Hsp. The conformational changes, including lid closure and modulation of the catalytic loop, represent the rate-limiting step of the chaperone cycle of Hsp (Figure 3).
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