β-arrestin1 and 2 adopt distinct phosphorylation-dependent conformations when coupling to the active parathyroid hormone 1 receptor in living cells.
β-arrestin1 and 2 adopt distinct phosphorylation-dependent conformations when binding to the same GPCR, providing a structural basis for their differential signaling roles.
β-arrestins mediate regulatory processes for over 800 different G protein-coupled receptors (GPCRs) by adopting specific conformations that result from the geometry of the GPCR-β-arrestin complex. However, whether β-arrestin1 and 2 respond differently for binding to the same GPCR is still unknown. Employing GRK knockout cells and β-arrestins lacking the finger-loop-region, we show that the two isoforms prefer to associate with the active parathyroid hormone 1 receptor (PTH1R) in different complex configurations ("hanging" and "core"). Furthermore, the utilisation of advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when bound to active PTH1R (P-R*). Moreover, we assess β-arrestin conformational changes that are induced specifically by proximal and distal C-terminal phosphorylation and in the absence of GPCR kinases (GRKs) (R*). Here, we show differences between conformational changes that are induced by P-R* or R* receptor states and further disclose the impact of site-specific GPCR phosphorylation on arrestin-coupling and function.
Haider et al. (Mon,) reported a other. PTH(1-34) vs. Vehicle/basal was evaluated on β-arrestin conformational changes measured by BRET. β-arrestin1 and 2 adopt distinct phosphorylation-dependent conformations when coupling to the active parathyroid hormone 1 receptor in living cells.