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

Janetzko, J.; Kise, R.; Barsi-Rhyne, B.; Siepe, D. H.; Heydenreich, F. M.; Masureel, M.; Kawakami, K.; Garcia, K. C.; Von Zastrow, M.; Inoue, A.; Kobilka, B. K.

doi:10.1101/2021.10.09.463790

bioRxiv · 10.1101/2021.10.09.463790

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

Janetzko, J.·Kise, R.·Barsi-Rhyne, B.·Siepe, D. H.·Heydenreich, F. M.·Masureel, M.·Kawakami, K.·Garcia, K. C.·Von Zastrow, M.·Inoue, A.·Kobilka, B. K.

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Abstract

Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized some GPCRs may complex with arrestin, while others interact transiently; this difference affects receptor signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in arrestin recruitment and GPCR-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one requiring PIP-binding for arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of arrestin and stabilize GPCR-arrestin complexes by promoting a receptor core-engaged state of the complex. As allosteric modulators of GPCR-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. The dependance on membrane PIPs provides a mechanism for arrestin release from transiently associated GPCRs, allowing their rapid recycling, while explaining how stably associated GPCRs are able to engage G proteins at endosomes.

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Janetzko, J., Kise, R., Barsi-Rhyne, B., Siepe, D. H., Heydenreich, F. M., Masureel, M., Kawakami, K., Garcia, K. C., Von Zastrow, M., Inoue, A., Kobilka, B. K.. 2021-10-10. Membrane phosphoinositides stabilize GPCR-arrestin complexes and offer temporal control of complex assembly and dynamics. https://doi.org/10.1101/2021.10.09.463790

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