| Structural highlights
Function
[TRAF6_HUMAN] E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [TIFA_HUMAN] Adapter protein which mediates the IRAK1 and TRAF6 interaction following IL-1 stimulation, resulting in the downstream activation of NF-kappa-B and AP-1 pathways. Induces the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism.[11] [12]
Publication Abstract from PubMed
Human tumor-necrosis-factor-receptor-associated factor (TRAF)-interacting protein with a forkhead-associated domain (TIFA) is a key regulator of NF-kappaB activation. It also plays a key role in the activation of innate immunity in response to bacterial infection, through heptose 1,7-bisphosphate (HBP), a metabolite of lipopolysaccharide (LPS). However, the mechanism of TIFA function is largely unexplored, except the suggestion for interacting with TRAF6. Here we provide evidence for direct binding, albeit weak, between TIFA and the TRAF domain of TRAF6, and show that the binding is enhanced for a rationally designed double mutant TIFA S174Q/M179D. The enhanced binding was also demonstrated for endogenous full-length TRAF6. Furthermore, we solved the structures of the TRAF domain complexes with the consensus TRAF-binding peptides from the C-terminus of wild-type and S174Q/M179D mutant TIFA, showing salt-bridge formation between residues 177-181 of TIFA and the binding pocket residues of the TRAF domain. Taken together, the results provide direct evidence and the structural basis for the TIFA-TRAF6 interaction, and show how this important biological function can be modulated.
Binding and Enhanced Binding between Key Immunity Proteins TRAF6 and TIFA.,Huang WC, Liao JH, Hsiao TC, Wei TW, Maestre-Reyna M, Bessho Y, Tsai MD Chembiochem. 2018 Oct 31. doi: 10.1002/cbic.201800436. PMID:30378729[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. TRAF6 is a signal transducer for interleukin-1. Nature. 1996 Oct 3;383(6599):443-6. PMID:8837778 doi:10.1038/383443a0
- ↑ Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000 Oct 13;103(2):351-61. PMID:11057907
- ↑ Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G. Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2006 Feb;7(2):139-47. Epub 2005 Dec 25. PMID:16378096 doi:10.1038/ni1294
- ↑ Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. J Biol Chem. 2007 Feb 9;282(6):4102-12. Epub 2006 Nov 29. PMID:17135271 doi:10.1074/jbc.M609503200
- ↑ Pham LV, Zhou HJ, Lin-Lee YC, Tamayo AT, Yoshimura LC, Fu L, Darnay BG, Ford RJ. Nuclear tumor necrosis factor receptor-associated factor 6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through small ubiquitin-related modifier-1 modification. J Biol Chem. 2008 Feb 22;283(8):5081-9. Epub 2007 Dec 19. PMID:18093978 doi:10.1074/jbc.M706307200
- ↑ Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landstrom M. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008 Oct;10(10):1199-207. doi: 10.1038/ncb1780. Epub 2008 Aug 31. PMID:18758450 doi:10.1038/ncb1780
- ↑ Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009 Sep 3;461(7260):114-9. doi: 10.1038/nature08247. Epub 2009 Aug 12. PMID:19675569 doi:10.1038/nature08247
- ↑ Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG, Lin HK. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 2009 Aug 28;325(5944):1134-8. doi: 10.1126/science.1175065. PMID:19713527 doi:10.1126/science.1175065
- ↑ Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, Du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H. Distinct molecular mechanism for initiating TRAF6 signalling. Nature. 2002 Jul 25;418(6896):443-7. PMID:12140561 doi:10.1038/nature00888
- ↑ Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich RL, Campos AD, Myszka DG, Lenardo MJ, Darnay BG, Wu H. E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 2009 Jun;16(6):658-66. Epub 2009 May 24. PMID:19465916 doi:10.1038/nsmb.1605
- ↑ Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J. Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling. J Biol Chem. 2003 Apr 4;278(14):12144-50. Epub 2003 Feb 3. PMID:12566447 doi:http://dx.doi.org/10.1074/jbc.M300720200
- ↑ Ea CK, Sun L, Inoue J, Chen ZJ. TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15318-23. Epub 2004 Oct 18. PMID:15492226 doi:http://dx.doi.org/0404132101
- ↑ Huang WC, Liao JH, Hsiao TC, Wei TW, Maestre-Reyna M, Bessho Y, Tsai MD. Binding and Enhanced Binding between Key Immunity Proteins TRAF6 and TIFA. Chembiochem. 2018 Oct 31. doi: 10.1002/cbic.201800436. PMID:30378729 doi:http://dx.doi.org/10.1002/cbic.201800436
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