Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders

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.

Insights into Hsp90 mechanism and in vivo functions learned from studies in the yeast, Saccharomyces cerevisiae

“…A yeast model system was previously used to test the functional link between glaucoma-associated mutations in the client WDR36 and the Hop/Sti1 cochaperone ( Footz et al, 2009 ; Footz et al, 2011 ). Mutations in multiple human Hsp90 cochaperones are associated with disease ( Johnson, 2021 ), some of which affect domains required for Hsp90 interaction ( Morgan et al, 2012 ). Future work is needed to determine whether mutations in the human homologs of proteins that crosslinked to Hsp90 are also linked to human disease.…”

“…The list of cochaperones continues to grow, with up to approximately 50 cochaperones identified in mammalian cells and approximately 14 in yeast ( Sahasrabudhe et al, 2017 ; Schopf et al, 2017 ; Backe et al, 2023a ). Mutations in some human cochaperones have been linked to a variety of disorders ( Dean and Johnson, 2021 ; Johnson, 2021 ). Results from the Lindquist lab and others suggest that some cochaperones have preference for clients with certain types of structural domains, such as the preference of Cdc37 for kinase domains ( Stuttmann et al, 2008 ; Taipale et al, 2012 ; Taipale et al, 2014 ; Verba and Agard, 2017 ; Schopf et al, 2019 ).…”

The Role of Glucocorticoid Receptor in the Pathophysiology of Pituitary Corticotroph Adenomas

“…HSP90, which under physiological stress conditions can represent up to 4–6% of total protein content [ 37 ], exerts its functions in concert with a number of co-chaperone proteins, such as HSF1, HSP70, p23, Hop, and Aha, forming so-called HSP90-containing protein complexes. Co-factors modulate HSP90 activity with several mechanisms—e.g., modulate ATPase activity or conformational change or targeted clients to HSP90 [ 38 ].…”

Nucleotide exchange is sufficient for Hsp90 functions in vivo

“…This idea is supported by observations that in vitro ATP does not induce conformational rearrangements like non-hydrolysable ATP analogs 6 , 13 – 16 . In vivo, these rearrangements are regulated by co-chaperones and post-translational modifications (reviewed in: 17 , 18 ). According to the current model of Hsp90 function, upon ATP hydrolysis the Hsp90 dimer returns to the open conformation, releasing the client, ADP and phosphate, thus resetting the reaction cycle 19 – 22 .…”