期刊
CELL
卷 185, 期 24, 页码 4560-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2022.10.018
关键词
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资金
- Mathers Foundation
- National Institutes of Health [K99GM147609, R01NS028471, R01AI125320, R01DA010711, R01DA012864]
- Chan-Zuckerberg Biohub
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation [DRG-2318-18]
- American Heart Association Predoctoral Fellowship [19PRE34380570]
- European Union [844622]
- American Heart Association postdoctoral fellowship [17POST33410958]
- Japan Agency for Medical Research and Development (AMED) [19gm5910013, 20gm0010004, JP20am0101095]
- KAKENHI from Japan Society for the Promotion of Science (JSPS) [17K08264, 21H04791, 21H05113, JPJSBP120213501, JPJSBP120218801]
- Takeda Science Foundation
- Ono Medical Research Foundation
- Uehara Memorial Foundation
- JST Moonshot Research and Development Program from the Japan Science and Technology Agency (JST) [JPMJMS2023]
- FOREST Program from the Japan Science and Technology Agency (JST) [JPMJFR215T]
- Daiichi Sankyo Foundation of Life Science
- Marie Curie Actions (MSCA) [844622] Funding Source: Marie Curie Actions (MSCA)
This study reveals the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics through cell-based and in vitro biophysical assays. GPCRs are classified into two groups, with one requiring PIP binding for β-arrestin recruitment and the other not. Plasma membrane PIPs enhance the active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for rapid β-arrestin release upon GPCR translocation to endosomes, enabling its quick recycling.
Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with (3-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in (3-arrestin recruitment and GPCR-(3-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for (3-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of (3-arrestin and stabilize GPCR-(3-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-(3-arrestin complex dynamics, membrane PIPs allow for additional confor-mational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for (3-arrestin recruitment, this provides a mechanism for (3-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.
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