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      Novel c-di-GMP recognition modes of the mouse innate immune adaptor protein STING.

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          Abstract

          The mammalian ER protein STING (stimulator of interferon genes; also known as MITA, ERIS, MPYS or TMEM173) is an adaptor protein that links the detection of cytosolic dsDNA to the activation of TANK-binding kinase 1 (TBK1) and its downstream transcription factor interferon regulatory factor 3 (IFN3). Recently, STING itself has been found to be the direct receptor of bacterial c-di-GMP, and crystal structures of several human STING C-terminal domain (STING-CTD) dimers in the apo form or in complex with c-di-GMP have been published. Here, a novel set of structures of mouse STING-CTD (mSTING(137-344)) in apo and complex forms determined from crystals obtained under different crystallization conditions are reported. These novel closed-form structures exhibited considerable differences from previously reported open-form human STING-CTD structures. The novel mSTING structures feature extensive interactions between the two monomers, a unique asymmetric c-di-GMP molecule with one guanine base in an unusual syn conformation that is well accommodated in the dimeric interface with many direct specific interactions and two unexpected equivalent secondary peripheral c-di-GMP binding sites. Replacement of the amino acids crucial for specific c-di-GMP binding in mSTING significantly changes the ITC titration profiles and reduces the IFN-β reporter luciferase activity. Taken together, these results reveal a more stable c-di-GMP binding mode of STING proteins that could serve as a template for rational drug design to stimulate interferon production by mammalian cells.

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          Author and article information

          Journal
          Acta Crystallogr. D Biol. Crystallogr.
          Acta crystallographica. Section D, Biological crystallography
          International Union of Crystallography (IUCr)
          1399-0047
          0907-4449
          Mar 2013
          : 69
          : Pt 3
          Affiliations
          [1 ] Agricultural Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan.
          Article
          S0907444912047269
          10.1107/S0907444912047269
          23519410

          c-di-GMP, π-helix, mouse STING, innate immune receptors

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