Demberg Lilian M, Winkler Jana, Wilde Caroline, Simon Kay-Uwe, Schön Julia, Rothemund Sven, Schöneberg Torsten, Prömel Simone, Liebscher Ines
From the Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry and.
the Core Unit Peptide Technologies, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
J Biol Chem. 2017 Mar 17;292(11):4383-4394. doi: 10.1074/jbc.M116.763656. Epub 2017 Jan 30.
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 sequence, can activate the respective receptor. As the conserved core region of the sequence is highly similar between aGPCRs, the agonist specificity of sequence-derived peptides was tested between family members using cell culture-based second messenger assays. 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 sequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, the -derived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in the sequence are very similar between aGPCRs allowing for agonist promiscuity of several -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 and studies. However, it also offers the possibility of a broader use of more potent peptides when the original sequence is less effective.
粘附G蛋白偶联受体（aGPCR）家族成员在其较大的胞外域中携带一个激动序列。源自该区域的肽段，称为序列，可激活相应的受体。由于aGPCR之间该序列的保守核心区域高度相似，因此使用基于细胞培养的第二信使测定法在家族成员之间测试了序列衍生肽的激动剂特异性。源自亚家族VI（GPR110/ADGRF1、GPR116/ADGRF5）和亚家族VIII（GPR64/ADGRG2、GPR126/ADGRG6）的aGPCR的肽段能够激活相应亚家族的多个成员，这支持了它们的进化关系，并将它们定义为药理学受体亚型。对该序列和衍生肽段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，而且在亚家族之间。例如，GPR110（亚家族VI）的衍生肽段可以激活GPR64和GPR126（均为亚家族VIII）。我们的结果表明，aGPCR之间该序列中的关键残基非常相似，使得几种衍生肽段具有激动剂混杂性。因此，aGPCR在药理学上的关系似乎比以前认为的更为密切。我们的发现对许多aGPCR研究有直接影响，因为在研究和时必须考虑潜在的功能重叠。然而，当原始序列效果较差时，这也提供了更广泛使用更有效肽段的可能性。
