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Structural basis for the tethered peptide activation of adhesion GPCRs.
- Source :
-
Nature [Nature] 2022 Apr; Vol. 604 (7907), pp. 763-770. Date of Electronic Publication: 2022 Apr 13. - Publication Year :
- 2022
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Abstract
- Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes <superscript>1-6</superscript> . Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence <superscript>7-12</superscript> . Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G <subscript>s</subscript> : GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W <superscript>6.53</superscript> and the constitution of a hydrogen-bond network formed by Q <superscript>7.49</superscript> /Y <superscript>7.49</superscript> and the P <superscript>6.47</superscript> /V <superscript>6.47</superscript> φφG <superscript>6.50</superscript> motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G <subscript>s</subscript> coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G <subscript>s</subscript> -binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G <subscript>s</subscript> . Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G <subscript>s</subscript> coupling.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 604
- Issue :
- 7907
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 35418678
- Full Text :
- https://doi.org/10.1038/s41586-022-04619-y