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Molecular determinants on extracellular loop domains that dictate interaction between β‐arrestin and human APJ receptor
Author(s) -
Ashokan Anisha,
Kameswaran Mythili,
Aradhyam Gopala Krishna
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13344
Subject(s) - extracellular , arrestin , microbiology and biotechnology , internalization , receptor , g protein coupled receptor , biology , mutant , phosphorylation , signal transduction , function (biology) , protein kinase b , biochemistry , gene
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 268 KTL 270 ‐AAA in ECL3 were deficient in all assays, whereas 183 MDYS 186 ‐AAAA mutant in ECL2 showed impaired β‐arrestin‐mediated signalling but demonstrated G i ‐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.