Activation of Adhesion G Protein-coupled Receptors AGONIST SPECIFICITY OF STACHEL SEQUENCE-DERIVED PEPTIDES
Activation of Adhesion G Protein-coupled Receptors AGONIST SPECIFICITY OF STACHEL SEQUENCE-DERIVED PEPTIDES
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DOI：
10.1074/jbc.m116.763656
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发表时间：
2017-03-10
影响因子：
4.8
通讯作者：
Liebscher, Ines
中科院分区：
文献类型：
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作者：
Demberg, Lilian M.;Winkler, Jana;Liebscher, Ines
粘附 G 蛋白偶联受体 (aGPCR) 家族的成员在其大胞外域内携带激动序列。源自该区域的肽（称为 Stachel 序列）可以激活相应的受体。由于 Stachel 序列的保守核心区域在 aGPCR 之间高度相似，因此使用基于细胞培养的第二信使测定在家族成员之间测试了 Stachel 序列衍生肽的激动剂特异性。源自 VI 亚家族（GPR110/ADGRF1、GPR116/ADGRF5）和 VIII 亚家族（GPR64/ADGRG2、GPR126/ADGRG6）aGPCR 的 Stachel 肽能够激活各自亚家族的多个成员，支持其进化关系并将其定义为药理学受体亚型。对 Stachel 序列和衍生肽的扩展功能分析揭示了激动剂的混杂性，不仅在 aGPCR 亚家族内部，而且在 aGPCR 亚家族之间也是如此。例如，GPR110（VI 亚家族）的 Stachel 衍生肽可以激活 GPR64 和 GPR126（均为 VIII 亚家族）。我们的结果表明，aGPCR 之间 Stachel 序列中的关键残基非常相似，从而允许几种 Stachel 衍生肽的激动剂混杂。因此，aGPCR 在药理学上的相关性似乎比之前认为的更为密切。我们的研究结果对许多 aGPCR 研究具有直接影响，因为体外和体内研究必须考虑潜在的功能重叠。然而，当原始 Stachel 序列效果较差时，它也提供了更广泛使用更有效的肽的可能性。
Members of the adhesion G protein-coupled receptor (aGPCR) family carry an agonistic sequence within their large ectodomains. Peptides derived from this region, called the Stachel sequence, can activate the respective receptor. As the conserved core region of the Stachel sequence is highly similar between aGPCRs, the agonist specificity of Stachel sequencederived peptides was tested between family members using cell culture-based second messenger assays. Stachel peptides derived from aGPCRs of subfamily VI (GPR110/ADGRF1, GPR116/ADGRF5) and subfamily VIII (GPR64/ADGRG2, GPR126/ADGRG6) are able to activate more than one member of the respective subfamily supporting their evolutionary relationship and defining them as pharmacological receptor subtypes. Extended functional analyses of the Stachel sequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, the Stachelderived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in the Stachel sequence are very similar between aGPCRs allowing for agonist promiscuity of several Stachel-derived peptides. Therefore, aGPCRs appear to be pharmacologically more closely related than previously thought. Our findings have direct implications for many aGPCR studies, as potential functional overlap has to be considered for in vitro and in vivo studies. However, it also offers the possibility of a broader use of more potent peptides when the original Stachel sequence is less effective.