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Publication Abstract from PubMed

Ric-8A is a cytosolic Guanine Nucleotide exchange Factor (GEF) that activates heterotrimeric G protein alpha subunits (Galpha) and serves as an essential Galpha chaperone. Mechanisms by which Ric-8A catalyzes these activities, which are stimulated by Casein Kinase II phosphorylation, are unknown. We report the structure of the nanobody-stabilized complex of nucleotide-free Galpha bound to phosphorylated Ric-8A at near atomic resolution by cryo-electron microscopy and X-ray crystallography. The mechanism of Ric-8A GEF activity differs considerably from that employed by G protein-coupled receptors at the plasma membrane. Ric-8A engages a specific conformation of Galpha at multiple interfaces to form a complex that is stabilized by phosphorylation within a Ric-8A segment that connects two Galpha binding sites. The C-terminus of Galpha is ejected from its beta sheet core, thereby dismantling the GDP binding site. Ric-8A binds to the exposed Galpha beta sheet and switch II to stabilize the nucleotide-free state of Galpha.

Structure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Galphai1.,McClelland LJ, Zhang K, Mou TC, Johnston J, Yates-Hansen C, Li S, Thomas CJ, Doukov TI, Triest S, Wohlkonig A, Tall GG, Steyaert J, Chiu W, Sprang SR Nat Commun. 2020 Feb 26;11(1):1077. doi: 10.1038/s41467-020-14943-4. PMID:32103024^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.