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Substitution of three amino acids switches receptor specificity of Gqα to that of Giα

Abstract

AGONIST-BOUND receptors activate heterotrimeric (αβγ) G proteins by catalysing replacement of GDP bound to the α-subunit by GTP1–5. Mutations in the C terminus of the α-subunit6,7, its covalent modification by pertussis toxin-catalysed ribosylation of ADP8, peptide-specific antibodies directed against it9–11, and peptides mimicking C-terminal sequences12, all inhibit receptor-mediated activation of G proteins. The logical prediction—that specific amino-acid residues at the C-termini of α-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 α-subunits (αq or αi) stimulate phosphatidylinositol-specific phospholipase C or inhibit adenylyl cyclase, respectively1–5. Here we replace C-terminal amino acids of αq with the corresponding residues of αi2 to create αqi2 chimaeras that can mediate stimulation of phospholipase C by receptors otherwise coupled exclusively to Gj. A minimum of three ai2 amino acids, including a glycine three residues from the C terminus, suffices to switch the receptor specificity of the αqi2 chimaeras. We propose that a C-terminal turn, centred on this glycine, plays an important part in specifying receptor interactions of G proteins in the Gi/G0/Gz family.

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Conklin, B., Farfel, Z., Lustig, K. et al. Substitution of three amino acids switches receptor specificity of Gqα to that of Giα. Nature 363, 274–276 (1993). https://doi.org/10.1038/363274a0

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