| Autor: |
Staus DP; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA., Hu H; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; School of Life and Health Sciences, Kobilka Institute of Innovative Drug Discovery, The Chinese University of Hong Kong, Shenzhen, China., Robertson MJ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Kleinhenz ALW; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA.; School of Medicine, University of Michigan, Ann Arbor, MI, USA., Wingler LM; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA., Capel WD; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Latorraca NR; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA.; Biophysics Program, Stanford University, Stanford, CA, USA., Lefkowitz RJ; Department of Medicine, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu., Skiniotis G; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu. |
| Abstrakt: |
After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis 1 . Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins 2 . In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of β-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of β-arrestin 1 (βarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of βarr1 to phosphorylated receptor residues and insertion of the finger loop of βarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G o protein complex 3 . Moreover, the cryo-electron microscopy map reveals that the C-edge of βarr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of β-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility. |
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