6o8c
Crystal structure of STING CTT in complex with TBK1Crystal structure of STING CTT in complex with TBK1
Structural highlights
FunctionTBK1_MOUSE Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFN-alpha and IFN-beta. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS or SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating IKKA/CHUK or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1 (By similarity).[1] [2] Publication Abstract from PubMedNucleic acids from bacteria or viruses induce potent immune responses in infected cells(1-4). The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses(5,6). Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor(7,8). It catalyses the synthesis of cyclic GMP-AMP (cGAMP)(9-12), which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis(13-15). STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase(8,16). The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK1(8,17-20). Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons(21). However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFNbeta after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1.,Zhao B, Du F, Xu P, Shu C, Sankaran B, Bell SL, Liu M, Lei Y, Gao X, Fu X, Zhu F, Liu Y, Laganowsky A, Zheng X, Ji JY, West AP, Watson RO, Li P Nature. 2019 May;569(7758):718-722. doi: 10.1038/s41586-019-1228-x. Epub 2019 May, 22. PMID:31118511[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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