Heterotrimeric G protein beta:gamma bound to a biologically active peptide : structural definition of a preferred protein interaction surface




Davis, Tara Lynne

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Heterotrimeric G proteins transmit information within and throughout eukaryotic cells. These proteins serve crucial functions in diverse signaling pathways, including visual transduction and adenylyl cyclase regulation. Heterotrimers are composed of α, β, and γ subunits. Gα is a guanosine triphosphatase (GTPase); Gβ and Gγ have no intrinsic enzymatic activity and form an obligate heterodimer that participates in independent signaling interactions when released from Gα. Gβγ signaling partners include Gα, phosphotidylinositol 3 kinase, phosducin, phospholipase C β, adenylyl cyclase, G protein receptor kinase, G protein regulated inwardly rectifying channels, and N and P/Q type calcium channels. The 2.7Å crystal structure of Gβ1γ2 bound to a peptide (SIGKAFKILGYPDYD) obtained from a random peptide library has been solved. This peptide inhibits Gβγ mediated activation of phospholipase C β and phosphatidylinositol-3-kinase γ and binds Gβ with sub-micromolar IC50. Gβ is a seven-stranded β-propeller protein containing WD-40 repeats. SIGK forms a helical structure that binds to the "top" face of the Gβ propeller. The peptide binds the same face of Gβ as Gα, and mutations of Gβ in this region abrogate peptide binding. In addition, the SIGK peptide binds Gβ using residues sampled by other Gβγ target proteins, both in crystal structures and in mutational analyses. No large conformational changes in Gβ are seen upon SIGK binding, and many of the biological effects seen for the SIGK peptide can be explained by simple competition for the top binding surface on Gβ. The SIGK peptide delineates a region on the "top" face of Gβ that is functionally a hot spot for Gβγ target binding. However, this face of Gβ contains a mixture of polar and nonpolar contacts at the binding surface that allows it to interact with proteins of diverse sequence and secondary structure in a unique way compared to other hot spot proteins. The SIGK•Gβ1γ2 structure provides insight into the way in which Gβ is able to sustain a range of interactions with multiple binding partners.

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