Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Structure. 2011 Feb 9;19(2):162-71. doi: 10.1016/j.str.2010.12.004.
Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side-chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as antideterminants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands.
诱饵受体 3（DcR3）是肿瘤坏死因子（TNF）受体超家族的一种分泌成员，能中和三种不同的 TNF 配体：FasL、LIGHT 和 TL1A。这些配体中的每一种都与独特的信号受体结合，从而引导不同的关键免疫反应。我们报告了未结合配体的 DcR3 胞外结构域及其与 TL1A 的复合物的晶体结构，以及互补的突变和生化研究。这些分析表明，DcR3 与 TL1A 的膜近端半部分的不变骨架和侧链原子相互作用，从而支持其识别三种不同的 TNF 配体。其他特征则作为反决定因素，阻止与 TNF 超家族的其他成员相互作用。这种相互作用模式在已鉴定的 TNF：TNFR 家族成员中是独特的，为支持 DcR3 的诱饵功能所需的广泛特异性以及 DcR3 及其配体的特异性和亲和力的合理操纵提供了机制基础。
