Structural basis for the tethered peptide activation of adhesion GPCRs
Structural basis for the tethered peptide activation of adhesion GPCRs
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粘附 GPCR 的束缚肽激活的结构基础
DOI：
10.1038/s41586-022-04619-y
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发表时间：
2022-04-13
期刊：
影响因子：
64.8
通讯作者：
Sun, Jin-Peng
中科院分区：
文献类型：
--
作者：
Ping, Yu-Qi;Xiao, Peng;Sun, Jin-Peng
黏附G蛋白偶联受体(AGPCRs)在器官发生、神经发育、生殖和其他过程中起重要作用(1-6)。许多aGPCRs被保守的内部(拴系的)激动剂序列激活，称为Stachel序列(7)(-1)(2)。在这里，我们报道了两个与G(S)形成的络合物：GPR133和GPR114的aGPCRs的低温电子显微镜结构。这些结构表明，这两种受体的Stachel序列都具有α-螺旋-凸起-β-折叠结构，并插入到由跨膜结构域(TMD)形成的结合部位。Stachel序列中的疏水相互作用基序(HIM)介导了与TMD的大部分分子内相互作用。结合冷冻-EM结构，HIM基序的生化表征提供了对Stachel序列的交叉反应和选择性的洞察。保守的“拨动开关”W-6.53对Stachel序列的感知以及由Q(7.49)/Y-7.49和P-6.47/V-6.47 Phi Phi G(6.50)基序组成的氢键网络(Phi表示疏水残基)在Stachel序列介导的受体激活和Gs偶联中是重要的两种相互联系的机制。值得注意的是，这个网络稳定了TM螺旋6和7(分别为TM6和TM7)的扭结形成。在两个aGPCR之间观察到一个共同的G(S)结合界面，GPR114具有一个延伸的TM7，与G(S)形成独特的相互作用。我们的结构揭示了Stachel序列及其G(S)偶联激活aGPCR的详细机制。
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)(-1)(2). 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 alpha-helical-bulge-beta-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 phi phi G(6.50) motif (phi indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs 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.