Establishing patterns of signaling

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Science Signaling  15 Dec 2020:
Vol. 13, Issue 662, eabg1206
DOI: 10.1126/scisignal.abg1206

The phosphorylation pattern of a GPCR C-terminal tail determines the effect on arrestin recruitment and conformation.

Ligand binding to G protein–coupled receptors (GPCRs) leads to the activation of G protein signaling, as well as the phosphorylation of intracellular residues by GPCR kinases, which facilitates the recruitment of arrestin proteins. The arrestins can desensitize GPCRs by blocking G protein coupling, facilitate GPCR internalization, and activate endosomal signaling pathways. Previous studies have established a so-called “barcode” hypothesis that suggests that distinct phosphorylation sites on the GPCR lead to the associated arrestin proteins performing different functions. Latorraca et al. have established the structural basis for this hypothesis by performing molecular dynamics simulations and site-directed spectroscopy to determine how phosphorylation of the V2 vasopressin receptor (V2R) at eight phosphorylatable residues in its C-terminal tail affected both the recruitment and conformation of β-arrestin1. Overall, the patterns of V2R phosphorylation affected arrestin binding and activation-associated conformational changes in distinct ways, and these effects depended to a greater extent on the spatial organization of the different phosphates than on their number. Thus, phosphorylation patterns that led to strong binding of arrestin did not necessarily cause arrestin to form an active conformation, and whether phosphorylation of a given residue stimulated or inhibited arrestin binding or activation depended on the other residues that were already phosphorylated. Together, these findings help to explain how drugs that bind to GPCRs can stimulate particular cellular functions by inducing distinct phosphorylation patterns that affect the binding and conformation of arrestins, which has consequences for downstream effectors.

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