Abstract
The Hsp90 molecular chaperone, along with a set of approximately 50 cochaperones, mediates the folding and activation of hundreds of cellular proteins in an ATP-dependent cycle. Cochaperones differ in how they interact with Hsp90 and their ability to modulate ATPase activity of Hsp90. Cochaperones often compete for the same binding site on Hsp90, and changes in levels of cochaperone expression that occur during neurodegeneration, cancer, or aging may result in altered Hsp90-cochaperone complexes and client activity. This review summarizes information about loss-of-function mutations of individual cochaperones and discusses the overall association of cochaperone alterations with a broad range of diseases. Cochaperone mutations result in ciliary or muscle defects, neurological development or degeneration disorders, and other disorders. In many cases, diseases were linked to defects in established cochaperone-client interactions. A better understanding of the functional consequences of defective cochaperones will provide new insights into their functions and may lead to specialized approaches to modulate Hsp90 functions and treat some of these human disorders.
Highlights
Cytosolic Hsp90 is an abundant and essential molecular chaperone that mediates the folding of hundreds of cellular proteins, called clients
The most complete model of Hsp90 function is based on an ATP-dependent cycle of glucocorticoid receptor (GR) folding
Unfolded GR bound to Hsp70 progresses through a loading complex consisting of Hsp70, Hsp90 and Hop to a mature complex consisting of folded GR, Hsp90, and p23
Summary
Cytosolic Hsp is an abundant and essential molecular chaperone that mediates the folding of hundreds of cellular proteins, called clients. Humans have two isoforms of cytosolic Hsp: Hsp90α (encoded by HSP90AA1), and Hsp90β (encoded by HSP90AB1) (Chen et al, 2006). While both isoforms are abundantly expressed, there are some tissue-specific differences in expression (Dean and Johnson, 2021). In addition to Hsp, client proteins interact with the molecular chaperone Hsp in an ordered cycle characterized by the presence of differing cochaperones. These cochaperones have a wide variety of functions, such as modulating Hsp ATPase activity or conformational changes or targeting clients to Hsp. Altered cochaperone levels and/or complexes have dramatic effects on GR activity (Reynolds et al, 1999; Echeverria et al, 2016)
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