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Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling
Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148833/ https://www.ncbi.nlm.nih.gov/pubmed/37120430 http://dx.doi.org/10.1038/s41467-023-38083-7 |
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author | Jones, Daniel T. D. Dates, Andrew N. Rawson, Shaun D. Burruss, Maggie M. Lipper, Colin H. Blacklow, Stephen C. |
author_facet | Jones, Daniel T. D. Dates, Andrew N. Rawson, Shaun D. Burruss, Maggie M. Lipper, Colin H. Blacklow, Stephen C. |
author_sort | Jones, Daniel T. D. |
collection | PubMed |
description | Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a previously reported Gα(q) preference by cryo-EM. Our structure shows that Gα(q) preference in ADGRF1 may derive from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helix VII and helix VIII at the site of Gα recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Gα(s) signalling is more sensitive to mutation of TA or binding site residues than Gα(q). Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation. |
format | Online Article Text |
id | pubmed-10148833 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101488332023-05-01 Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling Jones, Daniel T. D. Dates, Andrew N. Rawson, Shaun D. Burruss, Maggie M. Lipper, Colin H. Blacklow, Stephen C. Nat Commun Article Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a previously reported Gα(q) preference by cryo-EM. Our structure shows that Gα(q) preference in ADGRF1 may derive from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helix VII and helix VIII at the site of Gα recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Gα(s) signalling is more sensitive to mutation of TA or binding site residues than Gα(q). Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation. Nature Publishing Group UK 2023-04-29 /pmc/articles/PMC10148833/ /pubmed/37120430 http://dx.doi.org/10.1038/s41467-023-38083-7 Text en © The Author(s) 2023 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 Jones, Daniel T. D. Dates, Andrew N. Rawson, Shaun D. Burruss, Maggie M. Lipper, Colin H. Blacklow, Stephen C. Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title | Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title_full | Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title_fullStr | Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title_full_unstemmed | Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title_short | Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling |
title_sort | tethered agonist activated adgrf1 structure and signalling analysis reveal basis for g protein coupling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10148833/ https://www.ncbi.nlm.nih.gov/pubmed/37120430 http://dx.doi.org/10.1038/s41467-023-38083-7 |
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