title: Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-beta receptor.
abstract: Ligation of the lymphotoxin-beta receptor (LTbetaR) recruits tumor necrosis factor receptor-associated factor-3 (TRAF3) and initiates cell death in HT29 adenocarcinoma cells. The minimal receptor binding domain (TRAF-C) defined by two hybrid analyses is not sufficient for direct recruitment to the ligated receptor. A series of TRAF3 deletion mutants reveal that a subregion of the coiled coil motif is required for efficient recruitment to the LTbetaR. Furthermore, the ability of TRAF3 to self-associate maps to an adjacent subregion. A TRAF3 deletion mutant that lacks the N-terminal zinc RING and zinc finger motifs, but retains the coiled coil and TRAF-C motifs, competitively displaces endogenous TRAF3 from the LTbetaR. A second TRAF3 mutant that lacks the receptor binding domain, yet contains the TRAF3 self-association domain, prevents TRAF3 homodimers from being recruited to the LTbetaR. Both of these mutants have a dominant negative effect on cell death and demonstrate that the recruitment of TRAF3 oligomers is necessary to initiate signal transduction that activates the cell death pathway.
authors.affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Force
authors.forename: T C
authors.initials: TC
authors.lastname: Cheung
authors.forename: C F
authors.initials: CF
authors.lastname: Ware
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D053259:Lymphotoxin beta Receptor; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3; D016335:Zinc Fingers
chemical_list: C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3