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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-...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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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. |
format | Online Article Text |
id | pubmed-10400071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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