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G protein-coupled receptors (GPCRs) orchestrate diverse physiological responses via signaling through G proteins, GPCR kinases (GRKs), and arrestins. While most G protein functions are well-established, the contributions of GRKs and arrestins remain incompletely understood. Here, we investigate the influence of β-arrestin-interacting GPCR domains (helix-bundle/C-terminus) on β-arrestin conformations and functions using refined biosensors and advanced cellular knockout systems. Focusing on prototypical class A (b2AR) and B (V2R) receptors and their chimeras (b2V2/V2b2), we show that most N-domain β-arrestin conformational changes are mediated by receptor C-terminus-interactions, while C-domain conformations respond to the helix-bundle or an individual combination of interaction interfaces. Moreover, we demonstrate that ERK1/2 signaling responses are governed by the GPCR helix-bundle, while β-arrestin co-internalization depends on the receptor C-terminus. However, receptor internalization is controlled via the overall GPCR configuration. Our findings elucidate how individual GPCR domains dictate downstream signaling events, shedding light on the structural basis of receptor-specific signaling.
Matthees et al. (Tue,) studied this question.