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: Songying Ouyang, Xianqiang Song, Yaya Wang, Heng Ru, Neil Shaw, Yan Jiang, Fengfeng Niu, Yanping Zhu, Weicheng Qiu, Kislay Parvatiyar, Yang Li, Rongguang Zhang, Genhong Cheng, Zhi-Jie Liu
• Journal: Immunity (Immunity) Vol. 36 Issue 6 Pg. 1073-86 (Jun 29 2012) ISSN: 1097-4180 [Electronic] United States
• PMID: 22579474 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Peptide Fragments
• Recombinant Fusion Proteins
• STING1 protein, human
• bis(3',5')-cyclic diguanylic acid
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• Cyclic GMP

Topics

• Amino Acid Sequence
• Conserved Sequence
• Crystallography, X-Ray
• Cyclic GMP (analogs & derivatives, metabolism)
• Dimerization
• HEK293 Cells
• Humans
• Hydrophobic and Hydrophilic Interactions
• Membrane Proteins (chemistry, metabolism)
• Models, Molecular
• Molecular Sequence Data
• Peptide Fragments (chemistry, metabolism)
• Protein Binding
• Protein Conformation
• Protein Interaction Mapping
• Protein Serine-Threonine Kinases (metabolism)
• Recombinant Fusion Proteins (chemistry)
• Sequence Alignment
• Sequence Homology, Amino Acid
• Structure-Activity Relationship