Phosphorylation motif dictates GPCR C-terminal domain conformation and arrestin interaction

Guillien, M.; Mouhand, A.; Sagar, A.; Fournet, A.; Allemand, F.; Pereira, G. A. N.; Thureau, A.; Bernado, P.; Baneres, J.-L.; Sibille, N.

doi:10.1101/2023.02.23.529712

bioRxiv · 10.1101/2023.02.23.529712

Phosphorylation motif dictates GPCR C-terminal domain conformation and arrestin interaction

Guillien, M.·Mouhand, A.·Sagar, A.·Fournet, A.·Allemand, F.·Pereira, G. A. N.·Thureau, A.·Bernado, P.·Baneres, J.-L.·Sibille, N.

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Abstract

Arrestin dependent G protein-coupled receptor (GPCR) signaling pathway is regulated by the phosphorylation state of GPCRs C-terminal domain, but the molecular bases of arrestin:receptor interaction are to be further illuminated. Here we investigated the impact of phosphorylation on the conformational features of the C-terminal region from three Rhodopsin-like GPCRs, the vasopressin V2 Receptor (V2R), the Growth Hormone Secretagogue or ghrelin Receptor type 1a (GHSR) and the {beta}2-Adernergic Receptor ({beta}2AR). Using phosphomimetic variants, we identified pre-formed secondary structure elements, or short linear motif (SLiMs), that undergo specific conformational transitions upon phosphorylation. Of importance, such conformational transition favors arrestin-2 binding. Hence, our results suggest a model in which the cellular signaling specificity of GPCRs is encoded in the phosphorylation-dependent structuration of the C-terminal regions, which will subsequently modulate arrestin conformation and therefore GPCR:arrestin signaling outcomes.

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Guillien, M., Mouhand, A., Sagar, A., Fournet, A., Allemand, F., Pereira, G. A. N., Thureau, A., Bernado, P., Baneres, J.-L., Sibille, N.. 2023-02-23. Phosphorylation motif dictates GPCR C-terminal domain conformation and arrestin interaction. https://doi.org/10.1101/2023.02.23.529712

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