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.
Highlights
G protein-coupled receptors (GPCRs) are responsible for communication of the cell with surrounding environment
Molecular dynamics simulations were performed on wild-type arrestin1 and β -arrestin2 to examine the impact of the mutation on dynamics of the variant and determine its activation state
Wild-type β -arrestin2 displayed higher flexibility in the absence of any perturbation. This led to detachment of the loop from the protein in the variant as seen in crystal structures of receptor-bound and GPCR-phosphopeptide-bound arrestin (PDB IDs: 5W0P and 4JQI, respectively) [12,13]
Summary
G protein-coupled receptors (GPCRs) are responsible for communication of the cell with surrounding environment. Upon ligand binding the receptor undergoes a set of conformational changes which is recognized by heterotrimeric G protein. Depending on the type of the ligand certain cytosolic residues of the GPCR is phosphorylated by corresponding GPCR kinases. A protein which is responsible for GPCR-mediated signal termination, namely arrestin, is recruited to the membrane and it binds to the receptor. Occupation of the cytosolic region of the receptor by arrestin, which is otherwise occupied by the G protein, leads to desensitization [1]. 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]
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