8g2y
From Proteopedia
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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 Galpha(q) preference by cryo-EM. Our structure shows that Galpha(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 Galpha recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Galpha(s) signalling is more sensitive to mutation of TA or binding site residues than Galpha(q). Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation. | 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 Galpha(q) preference by cryo-EM. Our structure shows that Galpha(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 Galpha recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Galpha(s) signalling is more sensitive to mutation of TA or binding site residues than Galpha(q). Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation. | ||
| - | + | , PMID:37120430<ref>PMID:37120430</ref> | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Cryo-EM structure of ADGRF1 coupled to miniGs/q
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