Structural plasticity of arrestin-G protein coupled receptor complexes as a molecular determinant of signaling

G protein coupled receptors (GPCRs) are critically regulated by arrestins. In this study, high-resolution data was combined with molecular dynamics simulations to infer the determinants of (3-arrestin 1 ((3arr1)-GPCR coupling, using the V2 vasopressin receptor (V2R) as a model system. The study highlighted the extremely high plasticity of (3arr1-GPCR complexes, dependent on receptor type, state, and membrane environment. The multiple functions of receptor-bound (3arr1 are likely determined by the interplay of intrinsic flexibility and collective motions both as a bi-domain protein and as a whole. The two major collective motions of the whole (3arr1, consisting in rotation parallel to the membrane plane and inclination with respect to the receptor main axis, are distinctly linked to the two intermolecular interfaces involved in tail and core interactions. The intermolecular dynamic coupling between (3arr1 and V2R depends on the allosteric effect of the agonist arginine-vasopressin (AVP). In the absence of AVP the dynamic coupling concerns only tail interactions, while in the presence of AVP it involves both tail and core interactions. This suggests that constitutive and agonistinduced arrestin-receptor dynamic coupling is linked to distinct arrestin functions.