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首页> 外文期刊>Amino acids >The highly conserved negatively charged Glu141 and Asp145 of the G-protein-coupled receptor RXFP3 interact with the highly conserved positively charged arginine residues of relaxin-3
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The highly conserved negatively charged Glu141 and Asp145 of the G-protein-coupled receptor RXFP3 interact with the highly conserved positively charged arginine residues of relaxin-3

机译：G蛋白偶联受体RXFP3的高度保守的带负电的Glu141和Asp145与Relaxin-3的高度保守的带正电的精氨酸残基相互作用

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摘要

Relaxin-3 is a newly identified insulin/relaxin superfamily peptide that plays a putative role in the regulation of food intake and stress response by activating its cognate G-protein-coupled receptor R.XFP3. Relaxin-3 has three highly conserved arginine residues, B12Arg, B16Arg and B26Arg. We speculated that these positively charged arginines may interact with certain negatively charged residues of RXFP3. To test this hypothesis, we first replaced the negatively charged residues in the extracellular domain of RXFP3 with arginine, respectively. Receptor activation assays showed that arginine replacement of Glu141 or Asp145, especially Glu141, significantly decreased the sensitivity of RXFP3 to wild-type relaxin-3. In contrast, arginine replacement of other negatively charged extracellular residues had little effect. Thus, we deduced that Glu141 and Asp145, locating at the extracellular end of the second transmembrane domain, played a critical role in the interaction of RXFP3 with relaxin-3. To identify the ligand residues interacting with the negatively charged EXXXD motif of RXFP3, we replaced the three conserved arginines of relaxin-3 with negatively charged glutamate or aspartate, respectively. The mutant relaxin-3s retained the native structure, but their binding and activation potencies towards wild-type RXFP3 were decreased significantly. The compensatory effects of the mutant relaxin-3s towards mutant RXFP3s suggested two probable interaction pairs during ligand-receptor interaction: Glu141 of RXFP3 interacted with B26Arg of relaxin-3, meanwhile Asp 145 of RXFP3 interacted with both B12Arg and B16Arg of relaxin-3. Based on these results, we proposed a relaxin-3/RXFP3 interaction model that shed new light on the interaction mechanism of the relaxin family peptides with their receptors.
机译：Relaxin-3是一种新近鉴定的胰岛素/松弛素超家族肽，通过激活其关联的G蛋白偶联受体R.XFP3，在调节食物摄入和应激反应中起推定作用。 Relaxin-3具有三个高度保守的精氨酸残基，B12Arg，B16Arg和B26Arg。我们推测这些带正电荷的精氨酸可能与RXFP3的某些带负电荷的残基相互作用。为了验证该假设，我们首先分别用精氨酸替换了RXFP3胞外域中带负电荷的残基。受体激活试验表明，精氨酸替代Glu141或Asp145，尤其是Glu141可以显着降低RXFP3对野生型松弛素3的敏感性。相反，精氨酸替代其他带负电荷的细胞外残基影响不大。因此，我们推论位于第二跨膜结构域的细胞外端的Glu141和Asp145在RXFP3与Relaxin-3的相互作用中起着关键作用。为了鉴定与RXFP3带负电荷的EXXXD基序相互作用的配体残基，我们分别用带负电荷的谷氨酸或天冬氨酸取代了三个保守的松弛素-3精氨酸。突变体relaxin-3s保留了天然结构，但它们对野生型RXFP3的结合和激活能力却大大降低。突变体relaxin-3s对突变体RXFP3的补偿作用表明在配体-受体相互作用期间可能存在两个相互作用对：RXFP3的Glu141与relaxin-3的B26Arg相互作用，而RXFP3的Asp 145与relaxin-3的B12Arg和B16Arg相互作用。基于这些结果，我们提出了松弛素-3 / RXFP3相互作用模型，为松弛素家族肽与其受体的相互作用机理提供了新的思路。

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