CRYSTAL STRUCTURE OF DCR3-TL1A COMPLEX

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 诱骗受体3(DcR3)是一种分泌型免疫抑制蛋白，属于肿瘤坏死因子受体超家族。它的过度表达与癌症和自身免疫性疾病密切相关。对DcR3的S作用机制的剖析因其能够中和三种不同的肿瘤坏死因子配体：FasL、LIGHT和TL1a而变得复杂。这些配体中的每一个都与不同的功能受体结合，产生独特的免疫反应。明确DcR3及其配体之间的相互作用可能会为包括类风湿性关节炎、慢性疾病和恶性肿瘤在内的各种人类疾病提供新的治疗机会。在这里，我们报道了未连接的DcR3和DcR3-TL1a络合物的晶体结构。这些结构表明TL1a采用紧密的同源三聚体结构，而DcR3是一种具有新颖的富含半胱氨酸结构域的新型拉长的可溶性受体。每个DcR3分子都与两个相邻的TL1A亚基之间的凹槽结合，导致化学计量比为3：3。这种结构信息，与互补突变和生化特征相结合，揭示了一种不同于其他肿瘤坏死因子家族成员的受体识别模式。本研究解释了DcR3作为一种通用诱骗受体的结构基础，它中和了多个配体，并为涉及DcR3的免疫网络的功能注释提供了洞察。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Decoy Receptor 3 (DcR3) is a secreted immunosuppressive protein that belongs to the Tumor Necrosis Factor (TNF) receptor superfamily. Its overexpression has been closely linked to cancer and autoimmune diseases. The dissection of DcR3's functional mechanism is complicated by its ability to neutralize three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands binds distinct functional receptors, resulting in unique immune responses. Defining the interactions between DcR3 and its ligands may provide new therapeutic opportunities to a variety of human diseases, including rheumatoid arthritis, Chron's disease and malignancies. Here, we report the crystal structures of unliganded DcR3 and the DcR3-TL1A complex. These structures show that TL1A adopts a tight homotrimeric organization and that DcR3 is an elongated soluble receptor with novel cysteine-rich-domain module architecture. Each DcR3 molecule binds the groove between two adjacent TL1A subunits, resulting in a 3:3 stoichiometry. This structural information, in combination with complementary mutagenesis and biochemical characterization, reveals a mode of receptor recognition distinct from other TNF family members. This study explains the structural basis of DcR3 as a generic decoy receptor that neutralizes multiple ligands and provides insight into the functional annotation of the immunological network involving DcR3.