G protein-coupled receptors (GPCRs) are membrane receptors critically involved in sensing the environment and orchestrating physiological processes. As such, they transduce extracellular signals such as hormone, neurotransmitters, ions, and light into an integrated cell response. The intracellular trafficking, internalization, and signaling ability of ligand-activated GPCRs are controlled by arrestins, adaptor proteins that they interact with upon ligand binding. β-arrestins 1 and 2 in particular are now considered as hub proteins assembling multiprotein complexes to regulate receptor fate and transduce diversified cell responses. While more than 400 β-arrestin interaction partners have been identified so far, much remains to be learnt on how discrimination between so many binding partners is accomplished. Here, we gathered the interacting partners of β-arrestins through database mining and manual curation of the literature to map the β-arrestin interactome (β-arrestinome). We discussed several parameters that determine compatible (AND) or mutually exclusive (XOR) binding of β-arrestin interactors, such as structural constraints, intracellular abundance, or binding affinity.

This work was funded by the Agence Nationale de la Recherche GPCRnet project, by the Centre National de la Recherche Scientifique, by the Institut de la Recherche Agronomique PHASE Department, by the Région Centre, and by the European Commission (EC) Framework programme (FP) 7 project SynSignal (contract nr. 613879). LS is supported by the Spanish Ministerio de Economía y Competitividad, Plan Nacional BIO2012-39754, and the European Fund for Economic and Regional Development. LS and CK are particularly grateful for the support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017” (SEV-2012-0208).