Molecular determinants on extracellular loop domains that dictate interaction between β-arrestin and human APJ receptor

FEBS Letters

article

Anisha Ashokan¹  Mythili Kameswaran²  Gopala Krishna Aradhyam¹ 

[1] Signal Transduction Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras;Radiopharmaceuticals Division, Bhabha Atomic Research Centre

关键词: β-arrestin;    Akt phosphorylation;    apelin;    APJ receptor;    cell migration;    ;   

DOI  :  10.1002/1873-3468.13344

来源: John Wiley & Sons Ltd.

【 摘 要 】

The human APJ receptor (APJR), activated by apelin isoforms, regulates cardiovascular functions and fluid homeostasis. Understanding its structurefunction 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 b-arrestin-mediated signalling from human APJR: Apelin system. Alanine mutations of evolutionarily conserved residues were characterized using receptor internalization, b-arrestin pull-down, Akt phosphorylation and cell migration assay. C281A and 268KTL270-AAA in ECL3 were deficient in all assays, whereas 183MDYS186-AAAA mutant in ECL2 showed impaired b-arrestinmediated signalling but demonstrated Gi-dependent cell migration. Our findings establish that conserved residues in the extracellular domain play a prominent role in modulating receptor interactions with the b-arrestin signalling cascade.

【 授权许可】

Unknown