Residue-specific orientation of arrestin in 5-HTR1B (Serotonin Receptor)- βArrestin-1 interaction

Abstract

Physiologically G protein-coupled receptors (GPCRs) are an important class of cell surface proteins capable of sensing the exogenous signals across the cell membrane through G-protein-dependent and independent pathways. Activated GPCRs initiate diverse G-protein-independent signalling through interaction with arrestin. Arrestins comprise a family of four proteins that act as signal regulators of GPCRs. Arrestin specificity and assembly orientation with a particular GPCR depend on the finger loop's residues. Recent cryo-EM structural elucidation of neurotensin receptor-1(NTSR1)-β-arrestin1complex reveals its striking difference from Rhodopsin-visual-Arrestin by a 90˚ rotation of β-Arrestin1 concerning the receptor. Alignment of neurotensin receptor 1(NTSR1)-β-Arrestin1 assembly with 5-HTR1B (Serotonin receptor) structure shows an ionic interaction mediated complex formation between receptor binding cleft and finger loop of arrestin. Mutational analysis of finger loop residues R65, D67, and D69 of β-Arrestin1 by tango assay confirms its possible interaction with an electropositive pocket of K79 and R161 in 5-HTR1B.