Srivastava_2020_Bioessays__e1900208

Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a prominent non-receptor GEF and a chaperone of G protein alpha-subunits (Galpha). Recent studies shed light on the structure of Ric-8A, providing insights into the mechanisms underlying its interaction with Galpha. Ric-8A is composed of a core armadillo-like domain and a flexible C-terminal tail. Interaction of a conserved concave surface of its core domain with the Galpha C-terminus appears to mediate formation of the initial Ric-8A/GalphaGDP intermediate, followed by the formation of a stable nucleotide-free complex. The latter event involves a large-scale dislocation of the Galpha alpha5-helix that produces an extensive primary interface and disrupts the nucleotide-binding site of Galpha. The distal portion of the C-terminal tail of Ric-8A forms a smaller secondary interface, which ostensibly binds the switch II region of Galpha, facilitating binding of GTP. The two-site Galpha interface of Ric-8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric-8A.