Molecular Evolution of the Transmembrane Domains of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are a superfamily of integral membrane proteins vital for signaling and are important targets for pharmaceutical intervention in humans. Previously, we identified a group of ten amino acid positions (called key positions), within the seven transmembrane domain (7TM) interhelical region, which had high mutual information with each other and many other positions in the 7TM. Here, we estimated the evolutionary selection pressure at those key positions. We found that the key positions of receptors for small molecule natural ligands were under strong negative selection. Receptors naturally activated by lipids had weaker negative selection in general when compared to small molecule-activated receptors. Selection pressure varied widely in peptide-activated receptors. We used this observation to predict that a subgroup of orphan GPCRs not under strong selection may not possess a natural small-molecule ligand. In the subgroup of MRGX1-type GPCRs, we identified a key position, along with two non-key positions, under statistically significant positive selection.

G蛋白偶联受体（G protein-coupled receptors, GPCRs）是一类整合膜蛋白超家族，在信号转导中发挥关键作用，同时也是人类药物干预的重要靶点。此前，我们在七跨膜结构域（seven transmembrane domain, 7TM）的螺旋间区域中鉴定出10个氨基酸位点（称为关键位点），这些位点与7TM内的其他众多位点均存在较高的互信息。本研究对这些关键位点的进化选择压力进行了评估，发现结合小分子天然配体的受体其关键位点处于较强的负选择压力之下。相较于小分子激活型受体，天然由脂质激活的受体整体上负选择压力较弱；而肽激活型受体的选择压力差异则较为显著。基于上述观察，我们预测：未处于强选择压力下的孤儿GPCRs亚群，其天然配体可能并非小分子。在MRGX1型GPCRs亚群中，我们鉴定出1个关键位点以及2个非关键位点处于具有统计学显著性的正选择压力之下。