XB-ART-57003FEBS Lett 2019 Mar 01;5936:634-643. doi: 10.1002/1873-3468.13344.
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Molecular determinants on extracellular loop domains that dictate interaction between β-arrestin and human APJ receptor.
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 KTL270 -AAA in ECL3 were deficient in all assays, whereas 183 MDYS186 -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.
PubMed ID: 30801688
Article link: FEBS Lett
Species referenced: Xenopus laevis
Genes referenced: apln aplnr arrb1