Signal Transduction Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India.
FEBS Lett. 2019 Mar;593(6):634-643. doi: 10.1002/1873-3468.13344. Epub 2019 Mar 5.
The human APJ receptor (APJR), activated by apelin isoforms, regulates cardiovascular functions and fluid homeostasis. Understanding its structure-function relationship is crucial for a comprehensive knowledge of signalling aberrations that cause several physiological disorders. Here, we demonstrate the influence of extracellular loop (ECL) domains in the mechanism of β-arrestin-mediated signalling from human APJR: Apelin system. Alanine mutations of evolutionarily conserved residues were characterized using receptor internalization, β-arrestin pull-down, Akt phosphorylation and cell migration assay. C281A and KTL -AAA in ECL3 were deficient in all assays, whereas MDYS -AAAA mutant in ECL2 showed impaired β-arrestin-mediated signalling but demonstrated G -dependent cell migration. Our findings establish that conserved residues in the extracellular domain play a prominent role in modulating receptor interactions with the β-arrestin signalling cascade.
人 APJ 受体（APJR）被阿皮林异构体激活，调节心血管功能和液体稳态。了解其结构-功能关系对于全面了解导致多种生理紊乱的信号异常至关重要。在这里，我们展示了细胞外环（ECL）结构域在人 APJR 介导的β-arrestin 信号转导机制中的影响：阿皮林系统。使用受体内化、β-arrestin 下拉、Akt 磷酸化和细胞迁移测定法对进化保守残基的丙氨酸突变进行了表征。ECL3 中的 C281A 和 KTL-AAA 在所有测定中均缺失，而 ECL2 中的 MDYS-AAAA 突变体表现出受损的β-arrestin 介导的信号转导，但显示出 G 依赖性细胞迁移。我们的研究结果表明，细胞外结构域中的保守残基在调节受体与β-arrestin 信号级联的相互作用中起着重要作用。
