Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding
Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding
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DOI：
10.1038/s42003-020-0831-6
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发表时间：
2020-03-06
影响因子：
5.9
通讯作者：
Kim, Hee-Yong
中科院分区：
文献类型：
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作者：
Huang, Bill X.;Hu, Xin;Kim, Hee-Yong
Huang等人阐明了突触素激活粘附G蛋白偶联受体GPR 110的分子机制，突触素是已知的此类GPCR的唯一小分子内源性配体。他们通过化学交联质谱、建模和诱变发现，突触蛋白与GAIN结构域中的残基结合，并诱导构象变化触发下游信号传导。粘附G蛋白偶联受体（aGPCR）的特征在于含有保守的GPCR-自蛋白水解诱导（GAIN）结构域的大胞外区。尽管它们与几种疾病状况相关，但我们不了解aGPCR被生理激活的分子机制。GPR 110（ADGRF 1）是N-二十二碳六烯酸的突触生成代谢产物N-二十二碳六烯酸乙醇胺（N-docosahexaenoethanolamine，synaptase）的功能性受体。到目前为止，突触素是aGPCR的第一个也是唯一的小分子内源性配体。在这里，我们展示了突触素诱导的GPR 110在活细胞中激活的分子基础。使用细胞内化学交联/质谱，计算建模和诱变辅助功能测定，我们发现突触蛋白特异性结合GPR 110 GAIN亚结构域的接口，通过与残基Q511，N512和Y513的相互作用，导致细胞内构象变化附近的TM 6，触发下游信号。这种配体诱导的GAIN靶向激活机制为理解aGPCR的生理功能和GAIN结构域中的治疗靶向提供了框架。
Huang et al clarify the molecular mechanism of activation of adhesion G protein-coupled receptor GPR110 by synaptamide, the only small-molecule endogenous ligand known for this class of GPCR. They find through chemical cross-linking mass spectrometry, modeling and mutagenesis that synaptamide binds to residues in the GAIN domain and induces a conformational change triggering downstream signaling.Adhesion G protein-coupled receptors (aGPCR) are characterized by a large extracellular region containing a conserved GPCR-autoproteolysis-inducing (GAIN) domain. Despite their relevance to several disease conditions, we do not understand the molecular mechanism by which aGPCRs are physiologically activated. GPR110 (ADGRF1) was recently deorphanized as the functional receptor of N-docosahexaenoylethanolamine (synaptamide), a potent synaptogenic metabolite of docosahexaenoic acid. Thus far, synaptamide is the first and only small-molecule endogenous ligand of an aGPCR. Here, we demonstrate the molecular basis of synaptamide-induced activation of GPR110 in living cells. Using in-cell chemical cross-linking/mass spectrometry, computational modeling and mutagenesis-assisted functional assays, we discover that synaptamide specifically binds to the interface of GPR110 GAIN subdomains through interactions with residues Q511, N512 and Y513, causing an intracellular conformational change near TM6 that triggers downstream signaling. This ligand-induced GAIN-targeted activation mechanism provides a framework for understanding the physiological function of aGPCRs and therapeutic targeting in the GAIN domain.