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Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning

Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. For many receptors, how ligand sensitivity is fine-tuned and how disease associated mutations modulate receptor conformation to allosterically affect recept...

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Autores principales: Schamber, Michael R., Vafabakhsh, Reza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033857/
https://www.ncbi.nlm.nih.gov/pubmed/35459864
http://dx.doi.org/10.1038/s41467-022-29897-y
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author Schamber, Michael R.
Vafabakhsh, Reza
author_facet Schamber, Michael R.
Vafabakhsh, Reza
author_sort Schamber, Michael R.
collection PubMed
description Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. For many receptors, how ligand sensitivity is fine-tuned and how disease associated mutations modulate receptor conformation to allosterically affect receptor sensitivity are unknown. Here we map the activation of the calcium-sensing receptor (CaSR) - a dimeric class C G protein-coupled receptor (GPCR) and responsible for maintaining extracellular calcium in vertebrates. We show that CaSR undergoes unique conformational rearrangements compared to other class C GPCRs owing to specific structural features. Moreover, by analyzing disease associated mutations, we uncover a large permissiveness in the architecture of the extracellular domain of CaSR, with dynamics- and not specific receptor topology- determining the effect of a mutation. We show a structural hub at the dimer interface allosterically controls CaSR activation via focused electrostatic repulsion. Changes in the surface charge distribution of this hub, which is highly variable between organisms, finely tune CaSR sensitivity. This is potentially a general tuning mechanism for other dimeric receptors.
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spelling pubmed-90338572022-04-28 Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning Schamber, Michael R. Vafabakhsh, Reza Nat Commun Article Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. For many receptors, how ligand sensitivity is fine-tuned and how disease associated mutations modulate receptor conformation to allosterically affect receptor sensitivity are unknown. Here we map the activation of the calcium-sensing receptor (CaSR) - a dimeric class C G protein-coupled receptor (GPCR) and responsible for maintaining extracellular calcium in vertebrates. We show that CaSR undergoes unique conformational rearrangements compared to other class C GPCRs owing to specific structural features. Moreover, by analyzing disease associated mutations, we uncover a large permissiveness in the architecture of the extracellular domain of CaSR, with dynamics- and not specific receptor topology- determining the effect of a mutation. We show a structural hub at the dimer interface allosterically controls CaSR activation via focused electrostatic repulsion. Changes in the surface charge distribution of this hub, which is highly variable between organisms, finely tune CaSR sensitivity. This is potentially a general tuning mechanism for other dimeric receptors. Nature Publishing Group UK 2022-04-22 /pmc/articles/PMC9033857/ /pubmed/35459864 http://dx.doi.org/10.1038/s41467-022-29897-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Schamber, Michael R.
Vafabakhsh, Reza
Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title_full Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title_fullStr Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title_full_unstemmed Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title_short Mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
title_sort mechanism of sensitivity modulation in the calcium-sensing receptor via electrostatic tuning
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9033857/
https://www.ncbi.nlm.nih.gov/pubmed/35459864
http://dx.doi.org/10.1038/s41467-022-29897-y
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