title: Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding.
abstract: STING is an essential signaling molecule for DNA and cyclic di-GMP (c-di-GMP)-mediated type I interferon (IFN) production via TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway. It contains an N-terminal transmembrane region and a cytosolic C-terminal domain (CTD). Here, we describe crystal structures of STING CTD alone and complexed with c-di-GMP in a unique binding mode. The strictly conserved aa 153-173 region was shown to be cytosolic and participated in dimerization via hydrophobic interactions. The STING CTD functions as a dimer and the dimerization was independent of posttranslational modifications. Binding of c-di-GMP enhanced interaction of a shorter construct of STING CTD (residues 139-344) with TBK1. This suggests an extra TBK1 binding site, other than serine 358. This study provides a glimpse into the unique architecture of STING and sheds light on the mechanism of c-di-GMP-mediated TBK1 signaling.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Songying
authors.initials: S
authors.lastname: Ouyang
authors.forename: Xianqiang
authors.initials: X
authors.lastname: Song
authors.forename: Yaya
authors.initials: Y
authors.lastname: Wang
authors.forename: Heng
authors.initials: H
authors.lastname: Ru
authors.forename: Neil
authors.initials: N
authors.lastname: Shaw
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Niu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Weicheng
authors.initials: W
authors.lastname: Qiu
authors.forename: Kislay
authors.initials: K
authors.lastname: Parvatiyar
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Rongguang
authors.initials: R
authors.lastname: Zhang
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D008565:Membrane Proteins; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; C532857:STING1 protein, human; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid; C403191:TBK1 protein, human