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PDBsum entry 6u1n
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Signaling protein/immune system
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PDB id
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6u1n
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Contents |
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278 a.a.
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359 a.a.
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119 a.a.
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108 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of the m2 muscarinic receptor-β-Arrestin complex in a lipid nanodisc.
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Authors
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D.P.Staus,
H.Hu,
M.J.Robertson,
A.L.W.Kleinhenz,
L.M.Wingler,
W.D.Capel,
N.R.Latorraca,
R.J.Lefkowitz,
G.Skiniotis.
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Ref.
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Nature, 2020,
579,
297-302.
[DOI no: ]
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PubMed id
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Abstract
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After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit
β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes
receptor endocytosis1. Additionally, β-arrestin directly regulates
many cell signalling pathways that can induce cellular responses distinct from
that of G proteins2. 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
Go protein complex3. 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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