| Structural highlights
4im3 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 4im0, 4im2 |
| Gene: | TBK1, NAK (HUMAN) |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[TBK1_HUMAN] 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 NF-kappa-B inhibitor alpha/NFKBIA, IKBKB 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. Phosphorylates Borna disease virus (BDV) P protein.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) induces type I interferon expression and modulates nuclear factor kappaB (NF-kappaB) signaling. Here, we describe the 2.4 A-resolution crystal structure of nearly full-length TBK1 in complex with specific inhibitors. The structure reveals a dimeric assembly created by an extensive network of interactions among the kinase, ubiquitin-like, and scaffold/dimerization domains. An intact TBK1 dimer undergoes K63-linked polyubiquitination on lysines 30 and 401, and these modifications are required for TBK1 activity. The ubiquitination sites and dimer contacts are conserved in the close homolog inhibitor of kappaB kinase epsilon (IKKepsilon) but not in IKKbeta, a canonical IKK that assembles in an unrelated manner. The multidomain architecture of TBK1 provides a structural platform for integrating ubiquitination with kinase activation and IRF3 phosphorylation. The structure of TBK1 will facilitate studies of the atypical IKKs in normal and disease physiology and further the development of more specific inhibitors that may be useful as anticancer or anti-inflammatory agents.
Structure and ubiquitination-dependent activation of TANK-binding kinase 1.,Tu D, Zhu Z, Zhou AY, Yun CH, Lee KE, Toms AV, Li Y, Dunn GP, Chan E, Thai T, Yang S, Ficarro SB, Marto JA, Jeon H, Hahn WC, Barbie DA, Eck MJ Cell Rep. 2013 Mar 28;3(3):747-58. doi: 10.1016/j.celrep.2013.01.033. Epub 2013, Feb 28. PMID:23453972[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pomerantz JL, Baltimore D. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 1999 Dec 1;18(23):6694-704. PMID:10581243 doi:10.1093/emboj/18.23.6694
- ↑ Tojima Y, Fujimoto A, Delhase M, Chen Y, Hatakeyama S, Nakayama K, Kaneko Y, Nimura Y, Motoyama N, Ikeda K, Karin M, Nakanishi M. NAK is an IkappaB kinase-activating kinase. Nature. 2000 Apr 13;404(6779):778-82. PMID:10783893 doi:10.1038/35008109
- ↑ Kishore N, Huynh QK, Mathialagan S, Hall T, Rouw S, Creely D, Lange G, Caroll J, Reitz B, Donnelly A, Boddupalli H, Combs RG, Kretzmer K, Tripp CS. IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. J Biol Chem. 2002 Apr 19;277(16):13840-7. Epub 2002 Feb 11. PMID:11839743 doi:10.1074/jbc.M110474200
- ↑ Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003 May;4(5):491-6. PMID:12692549 doi:10.1038/ni921
- ↑ Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003 May 16;300(5622):1148-51. Epub 2003 Apr 17. PMID:12702806 doi:10.1126/science.1081315
- ↑ Mori M, Yoneyama M, Ito T, Takahashi K, Inagaki F, Fujita T. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J Biol Chem. 2004 Mar 12;279(11):9698-702. Epub 2003 Dec 31. PMID:14703513 doi:10.1074/jbc.M310616200
- ↑ Kuai J, Wooters J, Hall JP, Rao VR, Nickbarg E, Li B, Chatterjee-Kishore M, Qiu Y, Lin LL. NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach. J Biol Chem. 2004 Dec 17;279(51):53266-71. Epub 2004 Oct 13. PMID:15485837 doi:M411037200
- ↑ Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem. 2004 Dec 31;279(53):55633-43. Epub 2004 Oct 15. PMID:15489227 doi:10.1074/jbc.M409825200
- ↑ tenOever BR, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, Hemmi H, Yamamoto M, Akira S, Yeh WC, Lin R, Hiscott J. Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J Virol. 2004 Oct;78(19):10636-49. PMID:15367631 doi:10.1128/JVI.78.19.10636-10649.2004
- ↑ Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008 Aug 6;27(15):2135-46. doi: 10.1038/emboj.2008.126. Epub 2008 Jun 26. PMID:18583960 doi:10.1038/emboj.2008.126
- ↑ Da Q, Yang X, Xu Y, Gao G, Cheng G, Tang H. TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. J Immunol. 2011 Mar 1;186(5):3023-30. doi: 10.4049/jimmunol.1000262. Epub 2011, Jan 26. PMID:21270402 doi:10.4049/jimmunol.1000262
- ↑ Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6474-9. doi:, 10.1073/pnas.1016132108. Epub 2011 Apr 4. PMID:21464307 doi:10.1073/pnas.1016132108
- ↑ Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dotsch V, Bumann D, Dikic I. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011 Jul 8;333(6039):228-33. doi: 10.1126/science.1205405. Epub 2011 May, 26. PMID:21617041 doi:10.1126/science.1205405
- ↑ Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701. PMID:21138416 doi:10.1042/BJ20101701
- ↑ Tu D, Zhu Z, Zhou AY, Yun CH, Lee KE, Toms AV, Li Y, Dunn GP, Chan E, Thai T, Yang S, Ficarro SB, Marto JA, Jeon H, Hahn WC, Barbie DA, Eck MJ. Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28;3(3):747-58. doi: 10.1016/j.celrep.2013.01.033. Epub 2013, Feb 28. PMID:23453972 doi:http://dx.doi.org/10.1016/j.celrep.2013.01.033
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