Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha

Nature. 1993 May 20;363(6426):274-6. doi: 10.1038/363274a0.


Agonist-bound receptors activate heterotrimeric (alpha beta gamma) G proteins by catalysing replacement of GDP bound to the alpha-subunit by GTP. mutations in the C terminus of the alpha-subunit, its covalent modification by pertussis toxin-catalysed ribosylation of ADP, peptide-specific antibodies directed against it, and peptides mimicking C-terminal sequences, all inhibit receptor-mediated activation of G proteins. The logical prediction--that specific amino-acid residues at the C-termini of alpha-subunits can determine the abilities of individual G proteins to discriminate among specific subsets of receptors--has so far not been tested experimentally. Different hormone receptors specifically activate Gq or Gi, whose alpha-subunits (alpha q or alpha i) stimulate phosphatidylinositol-specific phospholipase C or inhibit adenylyl cyclase, respectively. Here we replace C-terminal amino acids of alpha q with the corresponding residues of alpha i2 to create alpha q/alpha i2 chimaeras that can mediate stimulation of phospholipase C by receptors otherwise coupled exclusively to Gi. A minimum of three alpha i2 amino acids, including a glycine three residues from the C terminus, suffices to switch the receptor specificity of the alpha q/alpha i2 chimaeras. We propose that a C-terminal turn, centered on this glycine, plays an important part in specifying receptor interactions of G proteins in the Gi/Go/Gz family.

Publication types

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

MeSH terms

  • Adenylate Cyclase Toxin
  • Amino Acid Sequence
  • Amino Acids / metabolism*
  • Animals
  • Cells, Cultured
  • Enzyme Activation
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Glycine / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Pertussis Toxin
  • Protein Conformation
  • Receptors, Cell Surface / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Type C Phospholipases / metabolism
  • Virulence Factors, Bordetella / pharmacology


  • Adenylate Cyclase Toxin
  • Amino Acids
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Virulence Factors, Bordetella
  • Pertussis Toxin
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Glycine