Details

Autor(en) / Beteiligte

• Barros-Álvarez, Ximena
• Nwokonko, Robert M.
• Vizurraga, Alexander
• Matzov, Donna
• He, Feng
• Papasergi-Scott, Makaía M.
• Robertson, Michael J.
• Panova, Ouliana
• Yardeni, Eliane Hadas
• Seven, Alpay B.
• Kwarcinski, Frank E.
• Su, Hongyu
• Peroto, Maria Claudia
• Meyerowitz, Justin G.
• Shalev-Benami, Moran
• Tall, Gregory G.
• Skiniotis, Georgios

Titel

The tethered peptide activation mechanism of adhesion GPCRs

Ist Teil von

• Nature (London), 2022-04, Vol.604 (7907), p.757-762

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Adhesion 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. Cryo-electron microscopy structures of GPR56 and latrophilin 3 show how the released tethered agonist peptide interacts with the transmembrane domain, suggesting a model for the activation mechanism of adhesion G-protein-coupled receptors.