The single nucleotide β -arrestin2 variant, A248T, resembles dynamical properties of activated arrestin

Abstract

β -arrestins are responsible for termination of G protein-coupled receptor (GPCR)-mediated signaling. Association of single nucleotide variants with onset of crucial diseases has made this protein family hot targets in the field ofGPCR-mediated pharmacology. However, impact of these mutations on function of these variants has remained elusive.In this study, structural and dynamical properties of one of β -arrestin2 (arrestin 3) variants, A248T, which has beenidentified in some cancer tissue samples, were investigated via molecular dynamics simulations. The results showed thatthe variant underwent structural rearrangements which are seen in crystal structures of active arrestin. Specifically, the“short helix” unravels and the “gate loop” swings forward as seen in crystal structures of receptor-bound and GPCRphosphopeptide-bound arrestin. Moreover, the “finger loop” samples upward position in the variant. Importantly, theseregions harbor crucial residues that are involved in receptor binding interfaces. Cumulatively, these local structuralrearrangements help the variant adopt active-like domain angle without perturbing the “polar core”. Considering thatphosphorylation of the receptor is required for activation of arrestin, A248T might serve as a model system to understandphosphorylation-independent activation mechanism, thus enabling modulation of function of arrestin variants which areactivated independent of receptor phosphorylation as seen in cancer.