Structural underpinnings of Ric8A function as a G-protein ?-subunit chaperone and guanine-nucleotide exchange factor.

ABSTRACT: Resistance to inhibitors of cholinesterase 8A (Ric8A) is an essential regulator of G protein ?-subunits (G?), acting as a guanine nucleotide exchange factor and a chaperone. We report two crystal structures of Ric8A, one in the apo form and the other in complex with a tagged C-terminal fragment of G?. These structures reveal two principal domains of Ric8A: an armadillo-fold core and a flexible C-terminal tail. Additionally, they show that the G? C-terminus binds to a highly-conserved patch on the concave surface of the Ric8A armadillo-domain, with selectivity determinants residing in the G? sequence. Biochemical analysis shows that the Ric8A C-terminal tail is critical for its stability and function. A model of the Ric8A/G? complex derived from crosslinking mass spectrometry and molecular dynamics simulations suggests that the Ric8A C-terminal tail helps organize the GTP-binding site of G?. This study lays the groundwork for understanding Ric8A function at the molecular level.

SUBMITTER: Srivastava D 

PROVIDER: S-EPMC6625990 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature