Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit

Ned Van Eps, Anita M. Preininger, Nathan Alexander, Ali I. Kaya, Scott Meier, Jens Meiler, Heidi E. Hammb, and Wayne L. Hubbell


In G-protein signaling, an activated receptor catalyzes GDP/GTP exchange on theGα subunit of a heterotrimeric G protein. In an initial step, receptor interaction with Gα acts to allosterically trigger GDP release from a binding site located between the nucleotide binding domain and a helical domain, but the molecular mechanism is unknown. In this study, site-directed spin labeling and double electron–electron resonance spectroscopy are employed to reveal a large-scale separation of the domains that provides a direct pathway for nucleotide escape. Cross-linking studies show that the domain separation is required for receptor enhancement of nucleotide exchange rates. The interdomain opening is coupled to receptor binding via the C-terminal helix of Gα, the extension of which is a high-affinity receptor binding element.


DOI


Journal: Proceedings of the National Academy of Sciences