Structure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1

Levi J. McClelland, Kaiming Zhang, Tung Chung Mou, Jake Johnston, Cindee Yates-Hansen, Shanshan Li, Celestine J. Thomas, Tzanko I. Doukov, Sarah Triest, Alexandre Wohlkonig, Gregory G. Tall, Jan Steyaert, Wah Chiu, Stephen R. Sprang

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13 Scopus citations

Abstract

Ric-8A is a cytosolic Guanine Nucleotide exchange Factor (GEF) that activates heterotrimeric G protein alpha subunits (Gα) and serves as an essential Gα 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 Gα 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 Gα at multiple interfaces to form a complex that is stabilized by phosphorylation within a Ric-8A segment that connects two Gα binding sites. The C-terminus of Gα is ejected from its beta sheet core, thereby dismantling the GDP binding site. Ric-8A binds to the exposed Gα beta sheet and switch II to stabilize the nucleotide-free state of Gα.

Original languageEnglish
Article number1077
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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