Abstract
Although class A seven-transmembrane helix (7TM) receptor hetero-oligomers have been proposed, information on the assembly and function of such higher-order hetero-oligomers is not available. Utilizing bioluminescence resonance energy transfer (BRET), bimolecular luminescence/fluorescence complementation (BiLC/BiFC), and BiLC/BiFC BRET in HEK293T cells, we provide evidence that chemokine (C-X-C motif) receptor 4, atypical chemokine receptor 3, α1a -adrenoceptor, and arginine vasopressin receptor 1A form hetero-oligomers composed of 2-4 different protomers. We show that hetero-oligomerization per se and ligand binding to individual protomers regulate agonist-induced coupling to the signaling transducers of interacting receptor partners. Our findings support the concept that receptor hetero-oligomers form supramolecular machineries with molecular signaling properties distinct from the individual protomers. These findings provide a mechanism for the phenomenon of context-dependent receptor function.
Keywords:
ACKR3; AVPR1A; CXCR4; receptor dimer; receptor hetero-oligomerization; ɑ1-adrenergic receptor.
© 2021 Federation of European Biochemical Societies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Chemokine CXCL12 / genetics
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Chemokine CXCL12 / metabolism*
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Chemokine CXCL12 / pharmacology
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Fluorescence Resonance Energy Transfer
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Gene Expression
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Genes, Reporter
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HEK293 Cells
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Humans
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Kinetics
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Luciferases / genetics
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Luciferases / metabolism
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Plasmids / chemistry
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Plasmids / metabolism
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Protein Binding / drug effects
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Protein Conformation
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Receptors, Adrenergic, alpha-1 / chemistry*
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Receptors, Adrenergic, alpha-1 / genetics
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, CXCR / chemistry*
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Receptors, CXCR / genetics
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Receptors, CXCR / metabolism
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Receptors, CXCR4 / chemistry*
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism
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Receptors, Vasopressin / chemistry*
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Receptors, Vasopressin / genetics
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Receptors, Vasopressin / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
Substances
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ACKR3 protein, human
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ADRA1A protein, human
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AVPR1A protein, human
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Bacterial Proteins
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CXCL12 protein, human
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CXCR4 protein, human
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Chemokine CXCL12
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Luminescent Proteins
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Receptors, Adrenergic, alpha-1
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Receptors, CXCR
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Receptors, CXCR4
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Receptors, Vasopressin
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Recombinant Fusion Proteins
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yellow fluorescent protein, Bacteria
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Luciferases