通过TNF家族成员TALL-1揭示的联体受体结合
Yingfang Liu1, Xia Hong, John Kappler
1Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Nature
|May 2, 2003
概括
瘤亡因子 (TNF) 配体TALL-1与B细胞成熟受体BCMA和BAFF-R相互作用. 晶体结构揭示了新的结合接口和结构模块,澄清了受体特异性.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 生物化学 生物化学
背景情况:
- 瘤亡因子 (TNF) 超级家族的配体和受体对于免疫细胞功能至关重要.
- TALL-1 (也称为BAFF或BLyS) 和它的受体 (BCMA,TACI,BAFF-R) 是B细胞成熟的关键调节者.
- TALL-1的功能形式涉及一种可溶性碎片 (sTALL-1),它组装成一种类似病毒的粒子.
研究的目的:
- 确定sTALL-1的高分辨率晶体结构与BCMA和BAFF-R.的细胞外域复合.
- 阐明STALL-1及其同类受体之间的相互作用的结构基础.
- 识别新的结构特征,并了解受体结合特异性的分子决定因素.
主要方法:
- 进行X射线晶体学以确定stALL-1/BCMA和stALL-1/BAFF-R复合物的结构.
- 序列对齐和结构建模用于分析保存区域和预测功能重要性.
- 定位突变发生和体外结合实验,以验证结构发现并评估结合特异性.
主要成果:
- 与BCMA和BAFF-R细胞外域复合的stALL-1的晶体结构分别在2.6 Å和2.5 Å分辨率下确定.
- 无论是BCMA还是BAFF-R外细胞域,都表现出类似于马的架构,这些架构与stALL-1单体上类似于马的表面结合.
- 在综合体内确定了三种新型结构模块 (D2,X2和N).
- 发现BAFF-R中的一个特定的二硫化物桥对其选择性结合TALL-1而不是相关的配体APRIL至关重要,并通过结合试验证实了这一点.
结论:
- 确定的结构为TALL-1受体相互作用提供了前所未有的原子层次的洞察力.
- 新的结构模块有助于理解TNF超级家族的连接体-受体识别.
- 这些发现突出了BAFF-R对TALL-1的特异性的结构基础,使其与APRIL区别开来.
- 这项工作为了解B细胞成熟调节和潜在的治疗向奠定了基础.
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