Structural and molecular characterization of a preferred protein interaction surface on G protein βγ subunits

Tara L. Davis, Tabetha M. Bonacci, Stephen R. Sprang, Alan V. Smrcka

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


G protein βγ subunits associate with many binding partners in cellular signaling cascades. In previous work, we used random-peptide phage display screening to identify a diverse family of peptides that bound to a common surface on Gβγ subunits and blocked a subset of Gβγ effectors. Later studies showed that one of the peptides caused G protein activation through a novel Gβγ-dependent, nucleotide exchange-independent mechanism. Here we report the X-ray crystal structure of Gβ1γ2 bound to this peptide, SIGK (SIGKAFKILGYPDYD), at 2.7 Å resolution. SIGK forms a helical structure that binds the same face of Gβ1 as the switch II region of Gα. The interaction interface can be subdivided into polar and nonpolar interfaces that together contain a mixture of binding determinants that may be responsible for the ability of this surface to recognize multiple protein partners. Systematic mutagenic analysis of the peptide-Gβ1 interface indicates that distinct sets of amino acids within this interface are required for binding of different peptides. Among these unique amino acid interactions, specific electrostatic binding contacts within the polar interface are required for peptide-mediated subunit dissociation. The data provide a mechanistic basis for multiple target recognition by Gβγ subunits with diverse functional interactions within a common interface and suggest that pharmacological targeting of distinct regions within this interface could allow for selective manipulation of Gβγ-dependent signaling pathways.

Original languageEnglish
Pages (from-to)10593-10604
Number of pages12
Issue number31
StatePublished - Aug 9 2005


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