7sf7
LPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex with G protein heterotrimer
Structural highlights
Publication Abstract from PubMedAdhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions(1). Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface(1). Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood(2-5). Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation. The tethered peptide activation mechanism of adhesion GPCRs.,Barros-Alvarez X, Nwokonko RM, Vizurraga A, Matzov D, He F, Papasergi-Scott MM, Robertson MJ, Panova O, Yardeni EH, Seven AB, Kwarcinski FE, Su H, Peroto MC, Meyerowitz JG, Shalev-Benami M, Tall GG, Skiniotis G Nature. 2022 Apr;604(7907):757-762. doi: 10.1038/s41586-022-04575-7. Epub 2022 , Apr 13. PMID:35418682[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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