Mapping the conformational landscape of the stimulatory heterotrimeric G protein

Heterotrimeric G proteins serve as membrane-associated signaling hubs, in concert with their cognate G-protein-coupled receptors. Fluorine nuclear magnetic resonance spectroscopy was employed to monitor the conformational equilibria of the human stimulatory G-protein α subunit (G s α) alone, in the...

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Bibliographic Details
Published in:	Nature structural & molecular biology Vol. 30; no. 4; pp. 502 - 511
Main Authors:	Huang, Shuya Kate, Picard, Louis-Philippe, Rahmatullah, Rima S. M., Pandey, Aditya, Van Eps, Ned, Sunahara, Roger K., Ernst, Oliver P., Sljoka, Adnan, Prosser, R. Scott
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-04-2023 Nature Publishing Group
Subjects:	101/6 631/535/878/1263 631/92/612/194 82/80 82/83 96/33 Adenosine Allosteric properties Biochemistry Biological Microscopy Biomedical and Life Sciences Fluorine G protein-coupled receptors GTP-Binding Protein alpha Subunits - chemistry GTP-Binding Protein alpha Subunits - metabolism GTP-Binding Protein alpha Subunits, Gs - metabolism Heterotrimeric GTP-Binding Proteins - metabolism Humans Life Sciences Lipid bilayers Lipids Magnetic resonance spectroscopy Membrane Biology Membranes Models, Molecular NMR NMR spectroscopy Nuclear magnetic resonance Nucleotides Peptide mapping Protein Binding Protein Conformation Protein Structure Proteins Receptors Spectroscopy Spectrum analysis
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Summary:	Heterotrimeric G proteins serve as membrane-associated signaling hubs, in concert with their cognate G-protein-coupled receptors. Fluorine nuclear magnetic resonance spectroscopy was employed to monitor the conformational equilibria of the human stimulatory G-protein α subunit (G s α) alone, in the intact G s αβ 1 γ 2 heterotrimer or in complex with membrane-embedded human adenosine A 2A receptor (A 2A R). The results reveal a concerted equilibrium that is strongly affected by nucleotide and interactions with the βγ subunit, the lipid bilayer and A 2A R. The α1 helix of G s α exhibits significant intermediate timescale dynamics. The α4β6 loop and α5 helix undergo membrane/receptor interactions and order–disorder transitions respectively, associated with G-protein activation. The αN helix adopts a key functional state that serves as an allosteric conduit between the βγ subunit and receptor, while a significant fraction of the ensemble remains tethered to the membrane and receptor upon activation. Fluorine nuclear magnetic resonance spectroscopy of the stimulatory heterotrimeric G protein reveals a conformational landscape shaped by interactions with nucleotides, the lipid bilayer and a G-protein-coupled receptor.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1545-9993 1545-9985
DOI:	10.1038/s41594-023-00957-1