Carrington Paul E, Sandu Cristinel, Wei Yufeng, Hill Justine M, Morisawa Gaku, Huang Ted, Gavathiotis Evridipis, Wei Yu, Werner Milton H
Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, Box 42, New York, New York 10021, USA.
Mol Cell. 2006 Jun 9;22(5):599-610. doi: 10.1016/j.molcel.2006.04.018.
The structure of FADD has been solved in solution, revealing that the death effector domain (DED) and death domain (DD) are aligned with one another in an orthogonal, tail-to-tail fashion. Mutagenesis of FADD and functional reconstitution with its binding partners define the interaction with the intracellular domain of CD95 and the prodomain of procaspase-8 and reveal a self-association surface necessary to form a productive complex with an activated "death receptor." The identification of a procaspase-specific binding surface on the FADD DED suggests a preferential interaction with one, but not both, of the DEDs of procaspase-8 in a perpendicular arrangement. FADD self-association is mediated by a "hydrophobic patch" in the vicinity of F25 in the DED. The structure of FADD and its functional characterization, therefore, illustrate the architecture of key components in the death-inducing signaling complex.
FADD的结构已在溶液中解析出来，结果显示死亡效应结构域（DED）和死亡结构域（DD）以正交、尾对尾的方式相互排列。对FADD进行诱变并与其结合伙伴进行功能重建，确定了它与CD95细胞内结构域和procaspase-8前结构域的相互作用，并揭示了与活化的“死亡受体”形成有效复合物所必需的自缔合表面。在FADD DED上鉴定出procaspase特异性结合表面，表明在垂直排列中它与procaspase-8的一个而非两个DED优先相互作用。FADD自缔合由DED中F25附近的一个“疏水补丁”介导。因此，FADD的结构及其功能表征阐明了死亡诱导信号复合物中关键成分的结构。
