FADD的结构及其与前半胱天冬酶-8的相互作用模式。

The structure of FADD and its mode of interaction with procaspase-8.

作者信息

Carrington Paul E, Sandu Cristinel, Wei Yufeng, Hill Justine M, Morisawa Gaku, Huang Ted, Gavathiotis Evridipis, Wei Yu, Werner Milton H

机构信息

Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, Box 42, New York, New York 10021, USA.

出版信息

Mol Cell. 2006 Jun 9;22(5):599-610. doi: 10.1016/j.molcel.2006.04.018.

DOI:10.1016/j.molcel.2006.04.018

PMID:16762833

Abstract

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.

摘要

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。