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Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling

Authors :
Daniel T. D. Jones
Andrew N. Dates
Shaun D. Rawson
Maggie M. Burruss
Colin H. Lipper
Stephen C. Blacklow
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-13 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract 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 Gαq preference by cryo-EM. Our structure shows that Gαq 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 Gαs signalling is more sensitive to mutation of TA or binding site residues than Gαq. Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.b163ebf0949a4b94ef195e08c79d5
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-38083-7