Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.
TRADD is a multifunctional signaling adaptor protein that is recruited to TNFR1 upon ligand binding. The C-terminal of TRADD comprises the "death domain" that is responsible for association of TNFR1 and other death domain-containing proteins such as FADD and RIP. The N-terminal domain (N-TRADD) promotes the recruitment of TRAF2 to TNFR1 by binding to the C-terminal of TRAF2, leading to the activation of JNK/AP1 and NF-kappa B. The solution structure of N-TRADD was determined, revealing a novel protein fold. A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways.
Musculoskeletal Science, Genetics Institute, Wyeth Research, Cambridge, Massachusetts 02140, USA. dtsao@genetics.com
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Tsao
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McDonagh
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Telliez
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Hsu
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Malakian
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Lin
D000595:Amino Acid Sequence; D001665:Binding Sites; D019013:CD40 Antigens / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D012996:Solutions; D020349:Surface Plasmon Resonance; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D013816:Thermodynamics
D019013:CD40 Antigens; D010446:Peptide Fragments; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D012996:Solutions; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2