Membrane phosphoinositides stabilize GPCR-arrestin complexes and offer temporal control of complex assembly and dynamics

J Janetzko, R Kise, B Barsi-Ryne, DH Siepe… - Biorxiv, 2021 - biorxiv.org
Biorxiv, 2021biorxiv.org
Arrestins recognize activated and phosphorylated G protein-coupled receptors (GPCRs) and
are responsible for promoting acute desensitization of receptors as well as their endocytosis.
As phosphatidylinositols have been shown to bind to components of the endocytic
machinery, including arrestins, we examined the role of phosphoinositide (PIP) binding in
GPCR-arrestin complexes. Using a PIP-binding-deficient mutant of arrestin we find that
GPCRs stratify into two groups based on whether arrestin-PIP-interactions are required for …
Summary
Arrestins recognize activated and phosphorylated G protein-coupled receptors (GPCRs) and are responsible for promoting acute desensitization of receptors as well as their endocytosis. As phosphatidylinositols have been shown to bind to components of the endocytic machinery, including arrestins, we examined the role of phosphoinositide (PIP) binding in GPCR-arrestin complexes. Using a PIP-binding-deficient mutant of arrestin we find that GPCRs stratify into two groups based on whether arrestin-PIP-interactions are required for arrestin recruitment to activated receptors. This requirement for arrestin-PIP-interactions depends on receptor phosphorylation, with receptors having more limited phosphorylation requiring arrestin-PIP-binding capacity. In vitro, this arrestin lipid binding functions to stabilize receptor-arrestin complexes and is crucial for promoting a core-engaged state of the complex. In the absence of a bound GPCR, PIP2, but not endosome resident PI(3)P, promotes conformational changes in arrestin that parallel activation, including movement of the finger and gate loops, but without release of the arrestin C-terminus. These results suggest a model for arrestin recruitment that depends on three components that each function to potentiate the conformation of arrestin: the GPCR core, phosphorylated GPCR C-terminus and membrane phosphoinositides. Integration of a phosphoinositide-dependence into arrestin-GPCR complex assembly provides a mechanism for release of arrestin from GPCRs with insufficient phosphorylation, allowing for their rapid recycling, while explaining how GPCRs that form stable complexes with arrestin can remain associated yet switch from desensitized to allowing G protein coupling in endosomes.
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