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Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism

Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence these important physiological processes have yet to be explored. We present the 3.9 Å resolution cryo-...

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Autores principales: Caveney, Nathanael A, Tsutsumi, Naotaka, Garcia, K Christopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400071/
https://www.ncbi.nlm.nih.gov/pubmed/37535399
http://dx.doi.org/10.7554/eLife.86784
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author Caveney, Nathanael A
Tsutsumi, Naotaka
Garcia, K Christopher
author_facet Caveney, Nathanael A
Tsutsumi, Naotaka
Garcia, K Christopher
author_sort Caveney, Nathanael A
collection PubMed
description Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence these important physiological processes have yet to be explored. We present the 3.9 Å resolution cryo-EM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90–Cdc37, this work shows the remarkable plasticity of Cdc37 to interact with a broad array of clients with significant sequence variation. Furthermore, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of membrane receptor guanylyl cyclase-targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other membrane receptor guanylyl cyclase-related conditions.
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spelling pubmed-104000712023-08-04 Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism Caveney, Nathanael A Tsutsumi, Naotaka Garcia, K Christopher eLife Biochemistry and Chemical Biology Membrane receptor guanylyl cyclases play a role in many important facets of human physiology, from regulating blood pressure to intestinal fluid secretion. The structural mechanisms which influence these important physiological processes have yet to be explored. We present the 3.9 Å resolution cryo-EM structure of the human membrane receptor guanylyl cyclase GC-C in complex with Hsp90 and its co-chaperone Cdc37, providing insight into the mechanism of Cdc37 mediated binding of GC-C to the Hsp90 regulatory complex. As a membrane protein and non-kinase client of Hsp90–Cdc37, this work shows the remarkable plasticity of Cdc37 to interact with a broad array of clients with significant sequence variation. Furthermore, this work shows how membrane receptor guanylyl cyclases hijack the regulatory mechanisms used for active kinases to facilitate their regulation. Given the known druggability of Hsp90, these insights can guide the further development of membrane receptor guanylyl cyclase-targeted therapeutics and lead to new avenues to treat hypertension, inflammatory bowel disease, and other membrane receptor guanylyl cyclase-related conditions. eLife Sciences Publications, Ltd 2023-08-03 /pmc/articles/PMC10400071/ /pubmed/37535399 http://dx.doi.org/10.7554/eLife.86784 Text en © 2023, Caveney et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Caveney, Nathanael A
Tsutsumi, Naotaka
Garcia, K Christopher
Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title_full Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title_fullStr Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title_full_unstemmed Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title_short Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
title_sort structural insight into guanylyl cyclase receptor hijacking of the kinase–hsp90 regulatory mechanism
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400071/
https://www.ncbi.nlm.nih.gov/pubmed/37535399
http://dx.doi.org/10.7554/eLife.86784
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