A novel domain within the 55 kd TNF receptor signals cell death.
Deletion mutagenesis of the intracellular region of the 55 kd TNF receptor (TNF-R1) identified an approximately 80 amino acid domain near the C-terminus responsible for signaling cytotoxicity. This domain shows weak homology with the intracellular domain of Fas antigen, a transmembrane polypeptide that can also initiate a signal for cytotoxicity. Alanine-scanning mutagenesis of TNF-R1 confirmed that many of the amino acids conserved with Fas antigen are critical for the cytotoxic signal. This region of TNF-R1-Fas homology is therefore likely to define a novel domain (death domain) that signals programmed cell death. Mutations within the death domain of TNF-R1 also disrupted its ability to signal anti-viral activity and nitric oxide (NO) synthase induction. In addition, large deletions in the membrane-proximal half of the intracellular domain did not block signaling of cytotoxicity or anti-viral activity but did block induction of NO synthase.
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080.
L A
LA
Tartaglia
T M
TM
Ayres
G H
GH
Wong
D V
DV
Goeddel
D000595:Amino Acid Sequence; D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D016923:Cell Death / Q000502:physiology*; D002999:Clone Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007739:L Cells; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000633:toxicity; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma