The single nucleotideβ-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 of GPCR-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 been identified in some cancer tissue samples, were investigated via molecular dynamics simulations. The results showed that the 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 GPCR phosphopeptide-bound arrestin. Moreover, the "finger loop" samples upward position in the variant. Importantly, these regions harbor crucial residues that are involved in receptor binding interfaces. Cumulatively, these local structural rearrangements help the variant adopt active-like domain angle without perturbing the "polar core". Considering that phosphorylation of the receptor is required for activation of arrestin, A248T might serve as a model system to understand phosphorylation-independent activation mechanism, thus enabling modulation of function of arrestin variants which are activated independent of receptor phosphorylation as seen in cancer. of the receptor by arrestin, which is otherwise occupied by the G protein, leads to desensitization [1]. Finally, receptor-arrestin complex is internalized and depending on the needs of the cell it is either recycled back to the membrane or directed to lysosome for degradation [2,3].Arrestin protein family consists of four members, namely arrestin 1, 2( β -arrestin1), 3( β -arrestin2), and 4. In spite of sharing a high degree of sequence similarity and conserved structural fold, which is composed of two * Correspondence: osensoy@medipol.edu.tr This work is licensed under a Creative Commons Attribution 4.0 International License.

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