美国哈佛医学院周界文和吴皓研组提出预配体结合状态的自抑制结构暗示了一种获得有效DR5受体激活的新策略。这一研究成果发表在2023年1月6日出版的国际学术期刊《细胞研究》上。

他们发现肿瘤坏死因子受体超家族(TNFRSF)的代表性成员死亡受体5 (DR5-ECD)的外部结构域在锚定在脂质双分子层时可以特异性自关联，他们报道了这种由核磁共振(NMR)确定的自关联结构。出乎意料的是，识别出两个不重叠的交互接口，它们可以传播到更高阶的集群。结构引导诱变表明所观察到的前配体关联结构在表达DR5的细胞上有表达。DR5预配体关联具有自抑制作用，因为部分解离预配体簇的单结构域抗体(sdAbs)可以使受体对其配体TRAIL敏感，甚至在TRAIL缺失的情况下诱导大量受体信号通路。与大多数需要多价结合才能聚集受体激活的激动性抗体不同，这些激动性sdAbs是单价的，特异性地作用于受体的低聚自抑制结构。

他们的数据表明，受体如DR5可以形成结构上定义的与信号不兼容的前簇，真正的激动剂应该破坏前配体簇，同时将其转化为信号产生簇。这一机制增强了人们对TNFRSF信号传递长期存在的问题的理解，并提出了通过靶向受体前配体聚类开发激动分子的新机遇。

研究人员表示，TNFRSF成员是重要的治疗靶点，可被激活诱导癌细胞死亡或刺激免疫细胞增殖。尽管长期以来，人们一直认为这些受体组装了人类疾病中显性干扰所必需的前配体相关状态，但迄今为止，这些状态尚未得到结构表征。

附：英文原文

Title: Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation

Author: Du, Gang, Zhao, Linlin, Zheng, Yumei, Belfetmi, Anissa, Cai, Tiantian, Xu, Boying, Heyninck, Karen, Van Den Heede, Kim, Buyse, Marie-Ange, Fontana, Pietro, Bowman, Michael, Lin, Lih-Ling, Wu, Hao, Chou, James Jeiwen

Issue&Volume: 2023-01-06

Abstract: Members of the tumor necrosis factor receptor superfamily (TNFRSF) are important therapeutic targets that can be activated to induce death of cancer cells or stimulate proliferation of immune cells. Although it has long been implicated that these receptors assemble preligand associated states that are required for dominant interference in human disease, such states have so far eluded structural characterization. Here, we find that the ectodomain of death receptor 5 (DR5-ECD), a representative member of TNFRSF, can specifically self-associate when anchored to lipid bilayer, and we report this self-association structure determined by nuclear magnetic resonance (NMR). Unexpectedly, two non-overlapping interaction interfaces are identified that could propagate to higher-order clusters. Structure-guided mutagenesis indicates that the observed preligand association structure is represented on DR5-expressing cells. The DR5 preligand association serves an autoinhibitory role as single-domain antibodies (sdAbs) that partially dissociate the preligand cluster can sensitize the receptor to its ligand TRAIL and even induce substantial receptor signaling in the absence of TRAIL. Unlike most agonistic antibodies that require multivalent binding to aggregate receptors for activation, these agonistic sdAbs are monovalent and act specifically on an oligomeric, autoinhibitory configuration of the receptor. Our data indicate that receptors such as DR5 can form structurally defined preclusters incompatible with signaling and that true agonists should disrupt the preligand cluster while converting it to signaling-productive cluster. This mechanism enhances our understanding of a long-standing question in TNFRSF signaling and suggests a new opportunity for developing agonistic molecules by targeting receptor preligand clustering.

DOI: 10.1038/s41422-022-00755-2

Source: https://www.nature.com/articles/s41422-022-00755-2