A novel site on the G alpha-protein that recognizes heptahelical receptors

Specific domains of the G-protein a subunit have been shown to control coup ling to heptahelical receptors, The extreme N and C termini and a region be tween alpha4 and alpha5 helices of the G-protein alpha subunit are known to determine selective interaction with the receptors, The metabotropic gluta mate receptor 2 activated both mouse G alpha (15) and its human homologue G alpha (16), whereas metabotropic glutamate receptor 8 activated G alpha (1 5) only. The extreme C-terminal 20 amino acid residues are identical betwee n the G alpha (15) and G alpha (16) and are therefore unlikely to be involv ed in coupling selectivity, Our data reveal two regions on G alpha (16) tha t inhibit its coupling to metabotropic glutamate receptor 8, On a three-dim ensional model, both regions are found in a close proximity to the extreme C terminus of G alpha (16). One module comprises alpha4 helix, alpha4-beta6 loop (L9 Loop), beta6 sheet, and alpha5 helix. The other, not described pr eviously, is located within the loop that links the N-terminal alpha helix to the beta1 strand of the Res-like domain of the alpha subunit, Coupling o f G alpha (16) protein to the metabotropic glutamate receptor 8 is partiall y modulated by each module alone, whereas both modules are needed to elimin ate the coupling fully.