Nature (London), 2022-04, Vol.604 (7907), p.763-770
2022
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- Autor(en) / Beteiligte
- Titel
- Structural basis for the tethered peptide activation of adhesion GPCRs
- Ist Teil von
- Nature (London), 2022-04, Vol.604 (7907), p.763-770
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes 1 – 6 . Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence 7 – 12 . Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G s : 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 6.53 and the constitution of a hydrogen-bond network formed by Q 7.49 /Y 7.49 and the P 6.47 /V 6.47 φφG 6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G s coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G s -binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G s . Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G s coupling. Adhesion GPCRs involved in cell and matrix interactions signal through a distinct self-cleavage, self-activation mechanism.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/s41586-022-04619-yTitel-ID: cdi_pubmed_primary_35418678
- Format
- –
- Schlagworte
- 101/28, 13/95, 14/1, 38/109, 38/77, 45/70, 631/45/535/1258/1259, 631/45/612/194, 82/16, 82/29, 82/80, 82/83, Adhesion, Binding Sites, Conserved sequence, Coupling, Cross-reactivity, Cryoelectron Microscopy, Electron microscopy, G protein-coupled receptors, Helices, Humanities and Social Sciences, Hydrogen, Hydrogen bonds, Hydrophobicity, Microscopy, multidisciplinary, Mutation, Organogenesis, Peptides, Protein Domains, Protein Structure, Secondary, Proteins, Receptor mechanisms, Receptors, Receptors, G-Protein-Coupled - metabolism, Science, Science (multidisciplinary), Selectivity, Structure-Activity Relationship