title: Mutational analysis and NMR studies of the death domain of the tumor necrosis factor receptor-1.
abstract: Tumor necrosis factor receptor-1 (TNFR-1) death domain (DD) is the intracellular functional domain responsible for the receptor signaling activities. To understand the transduction mechanism of TNFR-1 signaling we performed structural and functional analysis of the TNFR-DD. The secondary structure of the TNFR-DD shows that it consists of six anti-parallel alpha-helices. The determination of the topological fold and an extensive mutagenesis analysis revealed that there are two opposite faces that are involved in self-association and interaction with the TRADD death domain. Interestingly, the same critical residues in TNFR-DD are involved in both interactions. There is a good correlation between the binding activities of the mutant proteins and their cytotoxic activities. These results provide important insight into the molecular interactions mediating TNFR-DD self-association and subsequent recruitment of TRADD in the signaling activity of TNFR-1.
authors.affiliation: Department of Musculoskeletal Science, Genetics Institute, Cambridge, MA 02140, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Telliez
authors.forename: G Y
authors.initials: GY
authors.lastname: Xu
authors.forename: J D
authors.initials: JD
authors.lastname: Woronicz
authors.forename: S
authors.initials: S
authors.lastname: Hsu
authors.forename: J L
authors.initials: JL
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.forename: S F
authors.initials: SF
authors.lastname: Sukits
authors.forename: R
authors.initials: R
authors.lastname: Powers
authors.forename: L L
authors.initials: LL
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D047990:TNF Receptor-Associated Factor 1
chemical_list: D015703:Antigens, CD; D010446:Peptide Fragments; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D047990:TNF Receptor-Associated Factor 1