Illuminating the allosteric modulation of the calcium-sensing receptor

Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cel...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 35; pp. 21711 - 21722
Main Authors Yi, Ping, Zhao, Wenjing, Wu, Yuling, Acher, Francine, Pin, Jean-Philippe, Liu, Jianfeng, Rondar, Philippe
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 01.09.2020
Subjects
Activation
Allosteric properties
Allosteric Regulation - physiology
Amino acids
Binding Sites - genetics
Biological Sciences
Biosensors
Calcium
Calcium - metabolism
Calcium - physiology
Calcium ions
Calcium-sensing receptors
Conformation
Energy transfer
Fluorescence resonance energy transfer
Fluorescence Resonance Energy Transfer - methods
Humans
Life Sciences
Ligands
Modulators
Molecular Conformation
Mutation
Nutrients
Receptors
Receptors, Calcium-Sensing - metabolism
Receptors, Calcium-Sensing - physiology
Receptors, Calcium-Sensing - ultrastructure
Receptors, G-Protein-Coupled - metabolism
Signal Transduction
G protein-coupled receptor
calcium
amino acids
nutrient sensing
allosteric modulator
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Summary:Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+ alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+ activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response.
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Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute, Durham, NC, and approved July 23, 2020 (received for review December 18, 2019)
Author contributions: H.L., P.Y., J.-P.P., J.L., and P.R. designed research; H.L., P.Y., W.Z., Y.W., and F.A. performed research; H.L., P.Y., W.Z., Y.W., F.A., J.-P.P., J.L., and P.R. analyzed data; and H.L., J.-P.P., J.L., and P.R. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1922231117