Interaction mechanism of insulin-like peptide 5 with relaxin family peptide receptor 4.
Interaction mechanism of insulin-like peptide 5 with relaxin family peptide receptor 4.
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DOI：
10.1016/j.abb.2017.03.001
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发表时间：
2017-04
影响因子：
3.9
通讯作者：
Meng-Jun Hu;Dian Wei;X. Shao;Jia-hui Wang;Ya‐Li Liu;Zeng-guang Xu;Zhan-Yun Guo
中科院分区：
文献类型：
--
作者：
Meng-Jun Hu;Dian Wei;X. Shao;Jia-hui Wang;Ya‐Li Liu;Zeng-guang Xu;Zhan-Yun Guo
胰岛素样肽5（INSL 5）是属于胰岛素/松弛素超家族的肠肽激素。它通过激活松弛素家族肽受体4（RXFP 4）参与调节食物摄入和葡萄糖稳态。先前的研究表明，B链对于INSL 5对RXFP 4的活性是重要的。然而，B链残基的功能尚未得到系统的研究。在目前的工作中，我们进行了丙氨酸扫描诱变的B-链残基的人INSL 5，以获得他们的贡献的概述。这些INSL 5突变体与人RXFP 4的结合和活化测定鉴定了两个必需的暴露的B链C末端残基（B23 Arg和B24 Trp）和一个重要的暴露的中心B链残基（B16 Ile）。这三个决定簇残基与C-末端羧酸基团一起可能构成了一个中心受体结合补丁，在INSL 5结合过程中与RXFP 4形成关键的疏水和静电相互作用。一些其他暴露的残基，包括B10 Glu、B12 Ile、B13 Arg、B17 Tyr、B21 Ser和B22 Ser，对INSL 5功能的贡献较小。这些辅助残基分散在中心受体结合斑的边缘周围，从而在INSL 5表面上形成外周受体结合斑。我们的工作为研究INSL 5与RXFP 4的相互作用机制提供了新的思路。
Insulin-like peptide 5 (INSL5) is a gut peptide hormone belonging to the insulin/relaxin superfamily. It is implicated in the regulation of food intake and glucose homeostasis by activating relaxin family peptide receptor 4 (RXFP4). Previous studies have suggested that the B-chain is important for INSL5 activity against RXFP4. However, functionalities of the B-chain residues have not yet been systematically studied. In the present work, we conducted alanine-scanning mutagenesis of the B-chain residues of human INSL5 to obtain an overview of their contributions. Binding and activation assays of these INSL5 mutants with human RXFP4 identified two essential exposed B-chain C-terminal residues (B23Arg and B24Trp) and one important exposed central B-chain residue (B16Ile). These three determinant residues together with the C-terminal carboxylate moiety probably constitute a central receptor-binding patch that forms critical hydrophobic and electrostatic interactions with RXFP4 during INSL5 binding. Some other exposed residues, including B10Glu, B12Ile, B13Arg, B17Tyr, B21Ser, and B22Ser, made minor contributions to INSL5 function. These auxiliary residues are scattered around the edge of the central receptor-binding patch, and thus form a peripheral receptor-binding patch on the surface of INSL5. Our present work provides new insights into the interaction mechanism of INSL5 with its receptor RXFP4.