TY - JOUR
T1 - The tethered peptide activation mechanism of adhesion GPCRs
AU - Barros-Álvarez, Ximena
AU - Nwokonko, Robert M
AU - Vizurraga, Alexander
AU - Matzov, Donna
AU - He, Feng
AU - Papasergi-Scott, Makaía M
AU - Robertson, Michael J
AU - Panova, Ouliana
AU - Yardeni, Eliane Hadas
AU - Seven, Alpay B
AU - Kwarcinski, Frank E
AU - Su, Hongyu
AU - Peroto, Maria Claudia
AU - Meyerowitz, Justin G
AU - Shalev-Benami, Moran
AU - Tall, Gregory G
AU - Skiniotis, Georgios
N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/28
Y1 - 2022/4/28
N2 - 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 interactions1. 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 surface1. 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 understood2,3,4,5. 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.
AB - 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 interactions1. 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 surface1. 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 understood2,3,4,5. 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.
UR - http://www.scopus.com/inward/record.url?scp=85128176236&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-022-04575-7
DO - https://doi.org/10.1038/s41586-022-04575-7
M3 - مقالة
C2 - 35418682
SN - 0028-0836
VL - 604
SP - 757
EP - 762
JO - Nature
JF - Nature
IS - 7907
ER -