Tartaglia L A, Ayres T M, Wong G H, Goeddel D V
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080.
Cell. 1993 Sep 10;74(5):845-53. doi: 10.1016/0092-8674(93)90464-2.
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.
对55kd肿瘤坏死因子受体（TNF-R1）细胞内区域进行缺失诱变，发现在C端附近有一个约80个氨基酸的结构域，负责传递细胞毒性信号。该结构域与Fas抗原的细胞内结构域有较弱的同源性，Fas抗原是一种跨膜多肽，也能启动细胞毒性信号。对TNF-R1进行丙氨酸扫描诱变证实，许多与Fas抗原保守的氨基酸对细胞毒性信号至关重要。因此，TNF-R1-Fas同源性的这一区域可能定义了一个新的结构域（死亡结构域），该结构域可发出程序性细胞死亡的信号。TNF-R1死亡结构域内的突变也破坏了其传递抗病毒活性和诱导一氧化氮（NO）合酶的能力。此外，细胞内结构域膜近端一半的大片段缺失并未阻断细胞毒性或抗病毒活性的信号传递，但确实阻断了NO合酶的诱导。
