| Structural highlights
Function
[TRAF2_HUMAN] Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
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
Tumor necrosis factor receptor superfamily members convey signals that promote diverse cellular responses. Receptor trimerization by extracellular ligands initiates signaling by recruiting members of the tumor necrosis factor receptor-associated factor (TRAF) family of adapter proteins to the receptor cytoplasmic domains. We report the 2.4-A crystal structure of a 22-kDa, receptor-binding fragment of TRAF2 complexed with a functionally defined peptide from the cytoplasmic domain of the CD40 receptor. TRAF2 forms a mushroom-shaped trimer consisting of a coiled coil and a unique beta-sandwich domain. Both domains mediate trimerization. The CD40 peptide binds in an extended conformation with every side chain in contact with a complementary groove on the rim of each TRAF monomer. The spacing between the CD40 binding sites on TRAF2 supports an elegant signaling mechanism in which trimeric, extracellular ligands preorganize the receptors to simultaneously recognize three sites on the TRAF trimer.
Crystallographic analysis of CD40 recognition and signaling by human TRAF2.,McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8408-13. PMID:10411888[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999 May 15;13(10):1297-308. PMID:10346818
- ↑ Li X, Yang Y, Ashwell JD. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002 Mar 21;416(6878):345-7. PMID:11907583 doi:10.1038/416345a
- ↑ Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003 Aug 14;424(6950):793-6. PMID:12917689 doi:http://dx.doi.org/10.1038/nature01803
- ↑ 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
- ↑ Csomos RA, Brady GF, Duckett CS. Enhanced cytoprotective effects of the inhibitor of apoptosis protein cellular IAP1 through stabilization with TRAF2. J Biol Chem. 2009 Jul 31;284(31):20531-9. doi: 10.1074/jbc.M109.029983. Epub 2009, Jun 8. PMID:19506082 doi:10.1074/jbc.M109.029983
- ↑ Li S, Wang L, Dorf ME. PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination. Mol Cell. 2009 Jan 16;33(1):30-42. doi: 10.1016/j.molcel.2008.11.023. PMID:19150425 doi:10.1016/j.molcel.2008.11.023
- ↑ Blackwell K, Zhang L, Thomas GS, Sun S, Nakano H, Habelhah H. TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. Mol Cell Biol. 2009 Jan;29(2):303-14. doi: 10.1128/MCB.00699-08. Epub 2008 Nov 3. PMID:18981220 doi:10.1128/MCB.00699-08
- ↑ Sondarva G, Kundu CN, Mehrotra S, Mishra R, Rangasamy V, Sathyanarayana P, Ray RS, Rana B, Rana A. TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation. Cell Res. 2010 Jan;20(1):89-98. doi: 10.1038/cr.2009.125. Epub 2009 Nov 17. PMID:19918265 doi:10.1038/cr.2009.125
- ↑ Zhang L, Blackwell K, Shi Z, Habelhah H. The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaB. J Mol Biol. 2010 Feb 26;396(3):528-39. doi: 10.1016/j.jmb.2010.01.008. Epub 2010 , Jan 11. PMID:20064526 doi:10.1016/j.jmb.2010.01.008
- ↑ 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
- ↑ Sasai M, Tatematsu M, Oshiumi H, Funami K, Matsumoto M, Hatakeyama S, Seya T. Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathway. Mol Immunol. 2010 Mar;47(6):1283-91. doi: 10.1016/j.molimm.2009.12.002. Epub 2010, Jan 4. PMID:20047764 doi:10.1016/j.molimm.2009.12.002
- ↑ Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY, Maceyka M, Jiang H, Luo C, Kordula T, Milstien S, Spiegel S. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature. 2010 Jun 24;465(7301):1084-8. doi: 10.1038/nature09128. PMID:20577214 doi:10.1038/nature09128
- ↑ Yin Q, Lamothe B, Darnay BG, Wu H. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry. 2009 Nov 10;48(44):10558-67. PMID:19810754 doi:10.1021/bi901462e
- ↑ Zheng C, Kabaleeswaran V, Wang Y, Cheng G, Wu H. Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation. Mol Cell. 2010 Apr 9;38(1):101-13. PMID:20385093 doi:10.1016/j.molcel.2010.03.009
- ↑ McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8408-13. PMID:10411888
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