| Structural highlights
Disease
[TRAF3_HUMAN] Defects in TRAF3 are the cause of susceptibility to herpes simplex encephalitis 3 (HSE3) [MIM:614849]. A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome.[1]
Function
[TRAF3_HUMAN] Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.[2] [3] [4] [5] [6] [7] [TNR3_HUMAN] Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.[8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Lymphotoxin-beta receptor (LTbetaR) and CD40 are members of the tumor necrosis factor family of signaling receptors that regulate cell survival or death through activation of NF-kappaB. These receptors transmit signals through downstream adaptor proteins called tumor necrosis factor receptor-associated factors (TRAFs). In this study, the crystal structure of a region of the cytoplasmic domain of LTbetaR bound to TRAF3 has revealed an unexpected new recognition motif, 388IPEEGD393, for TRAF3 binding. Although this motif is distinct in sequence and structure from the PVQET motif in CD40 and PIQCT in the regulator TRAF-associated NF-kappaB activator (TANK), recognition is mediated in the same binding crevice on the surface of TRAF3. The results reveal structurally adaptive "hot spots" in the TRAF3-binding crevice that promote molecular interactions driving specific signaling after contact with LTbetaR, CD40, or the downstream regulator TANK.
Structurally distinct recognition motifs in lymphotoxin-beta receptor and CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling.,Li C, Norris PS, Ni CZ, Havert ML, Chiong EM, Tran BR, Cabezas E, Reed JC, Satterthwait AC, Ware CF, Ely KR J Biol Chem. 2003 Dec 12;278(50):50523-9. Epub 2003 Sep 29. PMID:14517219[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Perez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, Herman M, Cardon A, Durandy A, Bustamante J, Vallabhapurapu S, Bravo J, Warnatz K, Chaix Y, Cascarrigny F, Lebon P, Rozenberg F, Karin M, Tardieu M, Al-Muhsen S, Jouanguy E, Zhang SY, Abel L, Casanova JL. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity. 2010 Sep 24;33(3):400-11. doi: 10.1016/j.immuni.2010.08.014. Epub 2010 , Sep 9. PMID:20832341 doi:10.1016/j.immuni.2010.08.014
- ↑ He L, Grammer AC, Wu X, Lipsky PE. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. J Biol Chem. 2004 Dec 31;279(53):55855-65. Epub 2004 Sep 21. PMID:15383523 doi:10.1074/jbc.M407284200
- ↑ Liao G, Zhang M, Harhaj EW, Sun SC. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem. 2004 Jun 18;279(25):26243-50. Epub 2004 Apr 14. PMID:15084608 doi:10.1074/jbc.M403286200
- ↑ Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O'Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM. DUBA: a deubiquitinase that regulates type I interferon production. Science. 2007 Dec 7;318(5856):1628-32. Epub 2007 Nov 8. PMID:17991829 doi:10.1126/science.1145918
- ↑ Mao AP, Li S, Zhong B, Li Y, Yan J, Li Q, Teng C, Shu HB. Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem. 2010 Mar 26;285(13):9470-6. doi: 10.1074/jbc.M109.071043. Epub 2010 , Jan 22. PMID:20097753 doi:10.1074/jbc.M109.071043
- ↑ Bista P, Zeng W, Ryan S, Bailly V, Browning JL, Lukashev ME. TRAF3 controls activation of the canonical and alternative NFkappaB by the lymphotoxin beta receptor. J Biol Chem. 2010 Apr 23;285(17):12971-8. doi: 10.1074/jbc.M109.076091. Epub 2010, Feb 25. PMID:20185819 doi:10.1074/jbc.M109.076091
- ↑ Li S, Lu K, Wang J, An L, Yang G, Chen H, Cui Y, Yin X, Xie P, Xing G, He F, Zhang L. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010 May;338(1-2):11-7. doi: 10.1007/s11010-009-0315-y. Epub, 2009 Nov 24. PMID:19937093 doi:10.1007/s11010-009-0315-y
- ↑ Crowe PD, VanArsdale TL, Walter BN, Ware CF, Hession C, Ehrenfels B, Browning JL, Din WS, Goodwin RG, Smith CA. A lymphotoxin-beta-specific receptor. Science. 1994 Apr 29;264(5159):707-10. PMID:8171323
- ↑ Rooney IA, Butrovich KD, Glass AA, Borboroglu S, Benedict CA, Whitbeck JC, Cohen GH, Eisenberg RJ, Ware CF. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem. 2000 May 12;275(19):14307-15. PMID:10799510
- ↑ Li C, Norris PS, Ni CZ, Havert ML, Chiong EM, Tran BR, Cabezas E, Reed JC, Satterthwait AC, Ware CF, Ely KR. Structurally distinct recognition motifs in lymphotoxin-beta receptor and CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling. J Biol Chem. 2003 Dec 12;278(50):50523-9. Epub 2003 Sep 29. PMID:14517219 doi:10.1074/jbc.M309381200
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