Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system - PubMed (original) (raw)

Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system

Chang Shu et al. Nat Struct Mol Biol. 2012.

Abstract

STING (stimulator of interferon genes) is an innate immune sensor of cyclic dinucleotides that regulates the induction of type I interferons. STING's C-terminal domain forms a V-shaped dimer and binds a cyclic diguanylate monophosphate (c-di-GMP) at the dimer interface by both direct and solvent-mediated hydrogen bonds. Guanines of c-di-GMP stack against the phenolic rings of a conserved tyrosine, and mutations at the c-di-GMP binding surface reduce nucleotide binding and affect signaling.

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Figures

Figure 1

Figure 1

STING forms a dimer and binds c-di-GMP at the dimer interface. (a) C-di-GMP binding studies of human STING CTD (residues 149–341) by gel filtration chromatography. (b) C-di-GMP binding studies of STING CTD (residues 149 to 341) by ITC. (c) C-di-GMP binding studies of STING (residues 155 to 379) by ITC. (d) Structure of human STING CTD bound to c-di-GMP. STING is shown by the red and cyan ribbon representation. C-di-GMP is shown by the yellow ball and stick model.

Figure 2

Figure 2

Structural basis of c-di-GMP recognition and the dimer interface of STING. (a) Stereo close up of the c-di-GMP binding site of STING. Residues of STING are shown by the gray ball and stick models. C-di-GMP is shown by the cyan ball and stick model. Solvent molecules mediating hydrogen bonds between STING and c-di-GMP are shown by the red spheres. (b). Stereo close up view of the STING dimer interface. Residues at the dimer interface are shown by the gray and green stick models. (c) The Ca2+ binding sites between two STING dimers. Ca2+ ions are shown by the gray spheres and Ca2+ ligands are shown as gray sticks. Solvent molecules are shown by the red spheres. (d) Close up of the Ca2+ binding sites. Residues from one STING are shown by the gray ball and stick models. Residues from a symmetry-related STING are shown by the purple ball and stick models. Ca2+ are shown by the yellow spheres. Solvent molecules coordinating with the Ca2+ are shown by the blue spheres.

Figure 3

Figure 3

Mutations at the nucleotide binding surface reduce c-di-GMP binding and affect STING signaling. (a) C-di-GMP binding studies of wild-type and mutants of STING CTD by gel filtration chromatography. The inset shows a close up of the unbound c-di-GMP peaks. (b) C-di-GMP binding studies of STING mutants by ITC. (c) IFN-β luciferase assays show that mutations at the c-di-GMP binding surface affect signaling of mouse STING expressed in HEK293T cells. Residues Ile199, Tyr239, Asn241, Glu259, Thr262, Pro263, and Thr266 of mouse STING correspond to residues Ile200, Tyr240, Asn242, Glu260, Thr263, Pro264, and Thr267 of human STING. The error bars show standard deviations of signals from three independent transfections.

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References

    1. Keating SE, Baran M, Bowie AG. Trends Immunol. 2011;32:574–81. - PubMed
    1. Kato H, Takahasi K, Fujita T. Immunol Rev. 2011;243:91–8. - PubMed
    1. McWhirter SM, et al. J Exp Med. 2009;206:1899–911. - PMC - PubMed
    1. Woodward JJ, Iavarone AT, Portnoy DA. Science. 2010;328:1703–5. - PMC - PubMed
    1. Karaolis DK, et al. J Immunol. 2007;178:2171–81. - PubMed

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