AMINO-ACIDS 356-372 CONSTITUTE A G(I)-ACTIVATOR SEQUENCE OF THE ALPHA(2)-ADRENERGIC RECEPTOR AND HAVE A PHE SUBSTITUTE IN THE G-PROTEIN-ACTIVATOR SEQUENCE MOTIF

The human alpha2-adrenergic receptor contains the sequence KASRWRGRQNREKRFTF (amino acids 356-372) at the C-terminal end of its third intracellular loop. This sequence satisfies the structural criteria for G protein-activating sequences [(1992) J. Biol. Chem. 267, 8342-8346] except that the C-terminal sequence is B-B-X-X-Phe instead of B-B-X-B or B-B-X-X-B (B: basic residue, X: non-basic residue). Nevertheless, the synthetic peptide corresponding to this sequence (peptide alpha2-F) was found to activate G(i) and G(o) strongly with a saturated effect at 1-3 muM. Furthermore, the substitution of the C-terminal Phe of peptide alpha2-F with Arg, Trp, and Tyr (but not Ala or Asp) did not appreciably affect the G(i)-activating potency. It is suggested that the C-terminal basic residue of the B-B-X-X-B motif in G(i)-activating sequences can be replaced by an aromatic residue.