Structure and function studies of human STING and mouse STING

• Main Authors: Cheng-Kang Chen, 陳正鋼
• Other Authors: Shan-Ho Chou
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/72882160708019667187

碩士 === 國立中興大學 === 生物化學研究所 === 102 === The mammalian ER protein STING (stimulators of IFN genes; also known as MITA, ERIS, MPYS and TMEM173) is an adaptor protein linking detection of cytosolic dsDNA to activation of TANK binding kinase 1 (TBK1) and its downstream transcription factor IFN-regulator factor 3 (IRF3). Cyclic di-nucleotides (CDN) are unique bacterial second messenger molecules that are able to interact directly with STING to induce type I interferon production. Intriguingly, some CDN mimics effective in mouse antitumor therapy have also been found to interact with STING. Unexpectedly, only mouse, but not human STING, is able to bind and respond to these agents. This indicates that there are substantial inter-species differences between the human and mouse STINGs that demand more thorough investigations. Here we report the determination of the wild type or mutant type STING-CTD (refereed to STING hereafter) crystal structures in complexes with c-di-AMP. Three interesting issues have been raised in this study. First, c-di-AMP is found to form a more stable complex than c-di-GMP, although adenine lacks one functional group in the base. This indicates that STING is flexible enough to accommodate a variety of ligands with diverse structures. Second, we can now explain why mouse vascular disrupting agent CMA or DMXAA only interacts with mSTING, but not hSTING, simply by the fact that native mSTING structure adopts an intrinsically close form while the hSTING an intrinsically open form. mSTING can thus bind CDN without much energy penalty, but a much stronger CDN may be required to induce the closing of the wide dimeric interface of hSTING. Third, the hSTING V194G variant adopts a closed conformation and interacts with vascular disrupting agent DMXAA with moderate strength.