Molecular determinants on extracellular loop domains that dictate interaction between β‐arrestin and human APJ receptor
2019
Ashokan, Anisha | Kameswaran, Mythili | Aradhyam, Gopala Krishna
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 ²⁶⁸KTL²⁷⁰‐AAA in ECL3 were deficient in all assays, whereas ¹⁸³MDYS¹⁸⁶‐AAAA mutant in ECL2 showed impaired β‐arrestin‐mediated 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 β‐arrestin signalling cascade.
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