Conformational flexibility of β‐arrestins – How these scaffolding proteins guide and transform the functionality of GPCRs

G protein‐coupled receptors (GPCRs) constitute the largest family of transmembrane proteins and play a crucial role in regulating diverse cellular functions. They transmit their signaling via binding to intracellular signal transducers and effectors, such as G proteins, GPCR kinases, and β‐arrestins. To influence specific GPCR signaling behaviors, β‐arrestins recruit effectors to form larger signaling complexes. Intriguingly, they facilitate divergent functions for the binding to different receptors. Recent studies relying on advanced structural approaches, novel biosensors and interactome analyses bring us closer to understanding how this specificity is achieved. In this article, we share our hypothesis of how active GPCRs induce specific conformational rearrangements within β‐arrestins to reveal distinct binding interfaces, enabling the recruitment of a subset of effectors to foster specialized signaling complexes. Furthermore, we discuss methods of how to comprehensively assess β‐arrestin conformational states and present the current state of research regarding the functionality of these multifaceted scaffolding proteins. GPCRs play diverse roles in physiological processes by interacting with a limited number of transducers, like two β‐arrestin isoforms. Here, we elaborate how GPCR‐induced β‐arrestin conformational rearrangements enable the formation of signaling complexes that mediate specific cellular outcomes. This review emphasizes the significance of studying β‐arrestin conformations in GPCR signaling.