| Structural highlights
Function
[TRAF4_HUMAN] Adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. Plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. Regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. Required for normal skeleton development, and for normal development of the respiratory tract (By similarity). Required for activation of RPS6KB1 in response to TNF signaling. Modulates TRAF6 functions.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Tumor necrosis factor (TNF)-receptor associated factor 4 (TRAF4), an adaptor protein with E3-ligase activity, is involved in embryogenesis, cancer initiation and progression, and platelet receptor (GPIb-IX-V complex and GPVI)-mediated signaling for reactive oxygen species (ROS) production that initiates thrombosis at arterial shears. Disruption of platelet receptors and the TRAF4 interaction is a potential target for therapeutic intervention by antithrombotic drugs. Here, we report a crystal structure of TRAF4 (amino acid residues 290 approximately 470) in complex with a peptide from the GPIbbeta receptor (amino acid residues 177 approximately 181). The GPIbbeta peptide binds to a unique shallow surface composed of two hydrophobic pockets on TRAF4. Further studies revealed the TRAF4-binding motif Arg-Leu-X-Ala. The TRAF4-binding motif was present not only in platelet receptors but also in the TGF-beta receptor. The current structure will provide a template for furthering our understanding of the receptor-binding specificity of TRAF4, TRAF4-mediated signaling, and related diseases.
Molecular basis for unique specificity of human TRAF4 for platelets GPIbbeta and GPVI.,Kim CM, Son YJ, Kim S, Kim SY, Park HH Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11422-11427. doi:, 10.1073/pnas.1708688114. Epub 2017 Oct 10. PMID:29073066[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Xu YC, Wu RF, Gu Y, Yang YS, Yang MC, Nwariaku FE, Terada LS. Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase. J Biol Chem. 2002 Aug 2;277(31):28051-7. Epub 2002 May 22. PMID:12023963 doi:10.1074/jbc.M202665200
- ↑ Fleckenstein DS, Dirks WG, Drexler HG, Quentmeier H. Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk Res. 2003 Aug;27(8):687-94. PMID:12801526
- ↑ Takeshita F, Ishii KJ, Kobiyama K, Kojima Y, Coban C, Sasaki S, Ishii N, Klinman DM, Okuda K, Akira S, Suzuki K. TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. Eur J Immunol. 2005 Aug;35(8):2477-85. PMID:16052631 doi:10.1002/eji.200526151
- ↑ Abell AN, Johnson GL. MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J Biol Chem. 2005 Oct 28;280(43):35793-6. Epub 2005 Sep 12. PMID:16157600 doi:10.1074/jbc.C500260200
- ↑ Kedinger V, Alpy F, Baguet A, Polette M, Stoll I, Chenard MP, Tomasetto C, Rio MC. Tumor necrosis factor receptor-associated factor 4 is a dynamic tight junction-related shuttle protein involved in epithelium homeostasis. PLoS One. 2008;3(10):e3518. doi: 10.1371/journal.pone.0003518. Epub 2008 Oct 27. PMID:18953416 doi:10.1371/journal.pone.0003518
- ↑ 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
- ↑ Kim CM, Son YJ, Kim S, Kim SY, Park HH. Molecular basis for unique specificity of human TRAF4 for platelets GPIbbeta and GPVI. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11422-11427. doi:, 10.1073/pnas.1708688114. Epub 2017 Oct 10. PMID:29073066 doi:http://dx.doi.org/10.1073/pnas.1708688114
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