GPCR structure and function relationship: identification of a biased apelin receptor mutant

G蛋白偶联受体 受体 突变体 跨膜结构域 功能选择性 信号转导 细胞生物学 阿佩林 生物 G蛋白 化学 结合位点 逮捕 生物化学 基因
作者
Ting Ting Ban,Xun Li,Xiaochuan Ma,Hui Yang,Yunpeng Song,Yaping Sun,Michelle Shen,Na Li,Mei-Yun Zhang,Yingli Ma,Wenge Zhong,Mingqiang Zhang,Liaoyuan A. Hu
出处
期刊:Biochemical Journal [Portland Press]
卷期号:475 (23): 3813-3826 被引量:16
标识
DOI:10.1042/bcj20180740
摘要

Biased ligands of G protein-coupled receptors (GPCRs) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling. We discovered that a single residue mutation I109A (I1093.32) in the transmembrane domain 3 (TM3) located in the deep ligand-binding pocket was sufficient to convert a balanced APJ into a G protein signaling biased receptor. APJ I109A mutant receptor retained full capabilities in ligand binding and G protein activation, but was defective in GRK recruitment, β-arrestin recruitment, and downstream receptor-mediated ERK activation. Based on molecular dynamics simulations, we proposed a molecular mechanism for biased signaling of I109A mutant receptor. We postulate that due to the extra space created by I109A mutation, the phenyl group of the last residue (Phe-13) of apelin rotates down and initiates a cascade of conformational changes in TM3. Phe-13 formed a new cluster of hydrophobic interactions with the sidechains of residues in TM3, including F1103.33 and M1133.36, which stabilizes the mutant receptor in a conformation favoring biased signaling. Interruption of these stabilizing interactions by double mutation F110A/I109A or M113A/I109A largely restored the β-arrestin-mediated signaling. Taken together, we describe herein the discovery of a biased APJ mutant receptor and provide detailed molecular insights into APJ signaling selectivity, facilitating the discovery of novel therapeutics targeting APJ.
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