Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in
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PERSPECTIVE AND REFLECTION ARTICLE
Human Hsp90 cochaperones: perspectives on tissue-specific expression and identification of cochaperones with similar in vivo functions Marissa E. Dean 1 & Jill L. Johnson 1,2 Received: 14 July 2020 / Revised: 12 September 2020 / Accepted: 16 September 2020 # Cell Stress Society International 2020
Abstract The Hsp90 molecular chaperone is required for the function of hundreds of different cellular proteins. Hsp90 and a cohort of interacting proteins called cochaperones interact with clients in an ATP-dependent cycle. Cochaperone functions include targeting clients to Hsp90, regulating Hsp90 ATPase activity, and/or promoting Hsp90 conformational changes as it progresses through the cycle. Over the last 20 years, the list of cochaperones identified in human cells has grown from the initial six identified in complex with steroid hormone receptors and protein kinases to about fifty different cochaperones found in Hsp90-client complexes. These cochaperones may be placed into three groups based on shared Hsp90 interaction domains. Available evidence indicates that cochaperones vary in client specificity, abundance, and tissue distribution. Many of the cochaperones have critical roles in regulation of cancer and neurodegeneration. A more limited set of cochaperones have cellular functions that may be limited to tissues such as muscle and testis. It is likely that a small set of cochaperones are part of the core Hsp90 machinery required for the folding of a wide range of clients. The presence of more selective cochaperones may allow greater control of Hsp90 activities across different tissues or during development. Keywords Molecular chaperone . Hsp90 . Cochaperone . Tetratricopeptide repeat . Aha1 . Cdc37
The Hsp90 folding cycle The predominant model of Hsp90 and cochaperone interaction with client proteins is based on analysis of proteins that associate with steroid hormone receptors, such as the glucocorticoid receptor (GR). During GR folding and activation, Hsp90 progresses through a series of distinct complexes characterized by the presence of different cochaperones. This cycle was first established using cellular extracts and has since been confirmed using purified components. In a simplified model (Fig. 1a), the chaperones Hsp70 and Hsp40 interact Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12192-020-01167-0) contains supplementary material, which is available to authorized users. * Jill L. Johnson [email protected] 1
Department of Biological Sciences, University of Idaho, Moscow, ID 83844-3051, USA
2
Center for Reproductive Biology, University of Idaho, Moscow, ID 83844-3051, USA
with the client first. Hop (human gene name STIP1) is able to bind simultaneously to both Hsp70 and Hsp90, facilitating transfer of client to Hsp90. Coordinated action of Aha1 (human gene name AHSA1) and Cyp40 (human gene name PPID) displace Hop, allowing formation of the closed nucleotide-bound state characterized by interaction with p23 (human g
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