Human RGS 1 functionally complements a Saccharomyces cerevisiae mutant lacking the RGS homologue Sst2p. We demonstrate that deletion of the N-terminus or RGS domain negatively affects this ability in Sst2p-deficient strains, whereas deletion of the C-terminal 10 residues of RGS 1 does not. Coexpression of the N-terminus and RGS domains restores complementation of Sst2p to that of wild type. The conservative replacement of sequential residues spanning the N-terminus of RGS1 causes little loss of function. These results suggest that the N-terminal and RGS domains of RGS I function in concert to effect signaling and that the C-terminal 10 residues of RGS I are not required for this activity. Further, residues present in the N-terminus are not highly conserved suggesting that overall structure, rather than individual residues or motifs, may be important for function.