STRUCTURAL STUDIES OF TNFL-TNFR COMPLEXES INCLUDING BLYS-BR3

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。BlyS和April是肿瘤坏死因子（TNF）超家族的成员。它们都与受体TACI和BCMA结合，而只有BlyS与受体BR 3结合。BR 3和BCMA是TNF受体（TNFR）超家族的非常不同的成员，并且是已知的最小的TNFR，分别仅具有4个和6个半胱氨酸。在动物模型中，BLyS的过表达与外周B细胞的过度产生和系统性红斑狼疮样症状的发展有关。这些症状可以通过融合蛋白的治疗来缓解，所述融合蛋白由融合至TACI或BR 3的细胞外结构域（ECD）的Fc结构域组成。April还参与细胞增殖，并在某些肿瘤类型中过度表达。确定BLyS-BR 3复合物的高分辨率结构将使我们深入了解BR 3对4月份BLyS的特异性，将允许确定TNF-TNFR超家族信号传导的核心结构组分，并将有助于开发调节BLyS信号传导的药物，这些药物可能具有控制狼疮和其他自身免疫疾病的治疗潜力。

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. BlyS and April are members of the tumor necrosis factor (TNF) superfamily. They both bind to the receptors TACI and BCMA while only BlyS binds to the receptor BR3. BR3 and BCMA are very divergent members of the TNF receptor (TNFR) superfamily and are the smallest known TNFRs with only 4 and 6 cysteines each, respectively. Overexpression of BLyS has been implicated in the overproduction of peripheral B-cells and in the development of systemic lupus erythematosus-like symptoms in animal models. These symptoms can be alleviated with treatment by fusion proteins composed of an Fc domain fused to the extracellular domain (ECD) of TACI or BR3. April also is involved in cellular proliferation and is overexpressed by some tumor types. Determining the high-resolution structure of the BLyS-BR3 complex will give us insights into the specificity of BR3 for BLyS over April, will allow determination of the core structural components of TNF-TNFR superfamily signaling, and will assist in development agents to regulate BLyS signaling which may have therapeutic potential to control lupus and other auto-immune disorders.