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Structural insight into guanylyl cyclase receptor hijacking of the kinase–Hsp90 regulatory mechanism
Open accessPreprint — published as 10.7554/elife.86784.3 · Paper page
Abstract
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. Further, 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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
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Metadata
- Authors
- Caveney, N. A., Tsutsumi, N., & Garcia, K. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Caveney, Nathanael A
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-02-14
- PMC
- PMC9948968
- OpenAlex
- W4320922537
- Cited by
- 3
- References
- 2
- Citations by year
- 2025: 2 · 2024: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- G. Harold and Leila Y. Mathers Foundation
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute of Allergy and Infectious Diseases (R01AI051321)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- guanylyl cyclase C, HSP90, Cdc37, Hsp90 client proteins, receptor structure, hypertension, inflammatory bowel disease
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