| 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
Heterobifunctional molecules that induce targeted degradation have emerged as powerful tools in chemical biology, target validation, and drug discovery. Despite their promise, the field is constrained by the relative paucity of ligands available for E3 ligases. Expanding the ligand repertoire for E3 ligases and other components of ubiquitin-proteasome system could significantly broaden the scope of the targeted degradation field. In this study, we report the identification of ligands for non-essential E3 ligases that are preferentially expressed in cancer tissues relative to normal tissues. Using a protein-observed NMR-based fragment screen, an ideal technique for this purpose, we identified fragment ligands and characterized their binding modes by X-ray crystallography. These ligands represent promising starting points for further optimization toward the discovery of tumor-selective degraders that may enhance the therapeutic window targeting proteins for which inhibition or degradation is associated with systemic toxicity.
Identification of ligands for E3 ligases with restricted expression using fragment-based methods.,Waterson AG, Lehmann BD, Lu Z, Sensintaffar JL, Olejniczak ET, Zhao B, Rietz T, Payne WG, Phan J, Fesik SW RSC Chem Biol. 2025 Oct 2. doi: 10.1039/d5cb00198f. PMID:41070186[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
- ↑ Waterson AG, Lehmann BD, Lu Z, Sensintaffar JL, Olejniczak ET, Zhao B, Rietz T, Payne WG, Phan J, Fesik SW. Identification of ligands for E3 ligases with restricted expression using fragment-based methods. RSC Chem Biol. 2025 Oct 2. PMID:41070186 doi:10.1039/d5cb00198f
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