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

Nat Commun. 2019 Jul 12;10(1):3084. doi: 10.1038/s41467-019-11088-x.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Armadillo Domain Proteins / ultrastructure*
  • Cattle
  • GTP-Binding Protein alpha Subunits / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / ultrastructure*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Molecular Chaperones / ultrastructure*
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • Scattering, Small Angle
  • X-Ray Diffraction


  • Armadillo Domain Proteins
  • GTP-Binding Protein alpha Subunits
  • Guanine Nucleotide Exchange Factors
  • Molecular Chaperones
  • Recombinant Proteins