The tethered peptide activation mechanism of adhesion GPCRs.
The tethered peptide activation mechanism of adhesion GPCRs.
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DOI：
10.1038/s41586-022-04575-7
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发表时间：
2022-04
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
粘附G蛋白偶联受体（aGPCR）的特征在于存在参与细胞-细胞和细胞-细胞外基质相互作用的自蛋白水解胞外区（ECR）。在aGPCR自身蛋白水解诱导（GAIN）结构域内的自切割产生两个原聚体，N-末端和C-末端片段（NTF和CTF），其在受体到达细胞表面后保持非共价连接。在NTF解离后，GAIN结构域的C-末端作为拴系激动剂（TA）肽以激活7-跨膜（7TM）结构域，其机制尚不清楚。在这里，我们提供了aGPCR家族的两个不同成员，GPR56和Latrophilin-3（LPHN3）的cryo-EM快照。受体在其NTF结合状态下的低分辨率图表明GAIN结构域灵活地向细胞外空间投射，使加密的TA肽远离7TM。GPR56和LPHN3在其活性、G蛋白偶联状态下的高分辨率结构揭示，在ECR解离后，解密的TA肽与7TM核心接合，具有也涉及细胞外环2（ECL 2）的显著保守的相互作用。TA结合稳定了TM6和TM7中间的断裂，这有助于aGPCR偶联和异源三聚体G蛋白的活化。总的来说，这些结果使我们能够提出一个通用的模型aGPCR激活。
Adhesion G protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions (ECRs) involved in cell-cell and cell-extracellular matrix interactions. Self-cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers, N-terminal and C-terminal fragments (NTF and CTF), that remain non-covalently attached after receptors reach the cell surface. Upon NTF dissociation, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the 7-transmembrane (7TM) domain with a mechanism that has been poorly understood. Here we provide cryo-EM snapshots of two distinct members of the aGPCR family, GPR56 and Latrophilin-3 (LPHN3). Low resolution maps of the receptors in their NTF-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the 7TM. High resolution structures of GPR56 and LPHN3 in their active, G protein-coupled states, reveal that after ECR dissociation, the decrypted TA peptides engage the 7TM core with a remarkable conservation of interactions that also involve extracellular loop 2 (ECL2). TA binding stabilizes breaks in the middle of TM6 and TM7 that facilitates aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
64.5
作者：
Kim K;Che T;Panova O;DiBerto JF;Lyu J;Krumm BE;Wacker D;Robertson MJ;Seven AB;Nichols DE;Shoichet BK;Skiniotis G;Roth BL
通讯作者：
Roth BL
影响因子：
11.4
作者：
Arac, Demet;Boucard, Antony A.;Bolliger, Marc F.;Nguyen, Jenna;Soltis, S. Michael;Suedhof, Thomas C.;Brunger, Axel T.
通讯作者：
Brunger, Axel T.
影响因子：
64.5
作者：
Li J;Shalev-Benami M;Sando R;Jiang X;Kibrom A;Wang J;Leon K;Katanski C;Nazarko O;Lu YC;Südhof TC;Skiniotis G;Araç D
通讯作者：
Araç D
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML