Abstract
Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cattle
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Cryoelectron Microscopy
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Endosomes / metabolism
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / metabolism*
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GTP-Binding Proteins / ultrastructure
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Humans
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Models, Molecular
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Protein Conformation
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Receptors, Adrenergic, beta-2 / chemistry
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Receptors, Adrenergic, beta-2 / metabolism
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Receptors, Adrenergic, beta-2 / ultrastructure
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Receptors, G-Protein-Coupled / chemistry
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Receptors, G-Protein-Coupled / metabolism*
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Receptors, G-Protein-Coupled / ultrastructure
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Receptors, Vasopressin / chemistry
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Receptors, Vasopressin / metabolism
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Receptors, Vasopressin / ultrastructure
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Signal Transduction*
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beta-Arrestins / chemistry
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beta-Arrestins / metabolism*
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beta-Arrestins / ultrastructure
Substances
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Receptors, Adrenergic, beta-2
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Receptors, G-Protein-Coupled
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Receptors, Vasopressin
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arginine vasopressin receptor 2, human
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beta-Arrestins
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GTP-Binding Proteins