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Tethered agonist activated ADGRF1 structure reveals molecular preference for Gαq signalling

Daniel T. D. Jones, Andrew N. Dates, Shaun D. Rawson, Maggie M. Burruss, Colin H. Lipper, Stephen C. Blacklow
doi: https://doi.org/10.1101/2022.09.09.507336
Daniel T. D. Jones
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: stephen_blacklow@hms.harvard.edu daniel_jones@hms.harvard.edu
Andrew N. Dates
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Shaun D. Rawson
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Maggie M. Burruss
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Colin H. Lipper
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Stephen C. Blacklow
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
2Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
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  • For correspondence: stephen_blacklow@hms.harvard.edu daniel_jones@hms.harvard.edu
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Abstract

Adhesion G-Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to modulate cell signalling. We report here that ADGRF1 is the first class B GPCR shown to signal through all major G-protein classes and identify the structural basis for its Gαq preference by cryo-EM. Our structure shows that Gαq over Gαs preference in ADGRF1 derives from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helices VII and VIII at the site of Gα recruitment. Gαs signalling is also more sensitive to mutation of TA or binding site residues than Gαq. Our work advances the understanding of aGPCR TA activation in molecular detail, identifying structural features that potentially explain preferential signal modulation.

Competing Interest Statement

S.C.B. receives funding for an unrelated project from Novartis, is on the scientific advisory board for Erasca, Inc., is an advisor to MPM Capital, and is a consultant for IFM, Scorpion Therapeutics and Ayala Pharmaceuticals for unrelated projects.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted September 10, 2022.
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Tethered agonist activated ADGRF1 structure reveals molecular preference for Gαq signalling
Daniel T. D. Jones, Andrew N. Dates, Shaun D. Rawson, Maggie M. Burruss, Colin H. Lipper, Stephen C. Blacklow
bioRxiv 2022.09.09.507336; doi: https://doi.org/10.1101/2022.09.09.507336
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Tethered agonist activated ADGRF1 structure reveals molecular preference for Gαq signalling
Daniel T. D. Jones, Andrew N. Dates, Shaun D. Rawson, Maggie M. Burruss, Colin H. Lipper, Stephen C. Blacklow
bioRxiv 2022.09.09.507336; doi: https://doi.org/10.1101/2022.09.09.507336

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