Leibniz Institute for Age Research-Fritz Lipmann Institut, Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
J Mol Biol. 2011 Jun 3;409(2):189-201. doi: 10.1016/j.jmb.2011.03.048. Epub 2011 Apr 2.
Death receptors belong to the tumor necrosis factor receptor (TNFR) super family and are intimately involved in the signal transduction during apoptosis, stress response and cellular survival. Here we present the crystal structure of recombinantly expressed death receptor six (DR6), one family member that was recently shown to bind to the amyloid precursor protein (APP) and hence to be probably involved in the development of Alzheimer's disease. The extracellular cysteine rich region of DR6, the typical ligand binding region of all TNFRs, was refined to 2.2 Å resolution and shows that its four constituting cysteine rich domains (CRDs) are arranged in a rod-like overall structure, which presents DR6-specific surface patches responsible for the exclusive recognition of its ligand(s). Based on the structural data, the general ligand binding modes of TNFRs and molecular modeling experiments we were able to elucidate structural features of the potential DR6-APP signaling complex.
死亡受体属于肿瘤坏死因子受体（TNFR）超家族，在细胞凋亡、应激反应和细胞存活过程中的信号转导中起着重要作用。在这里，我们展示了重组表达的死亡受体六（DR6）的晶体结构，DR6 是最近被证明与淀粉样前体蛋白（APP）结合的家族成员之一，因此可能与阿尔茨海默病的发展有关。DR6 的细胞外富含半胱氨酸区域，是所有 TNFR 的典型配体结合区域，其分辨率被细化到 2.2Å，并表明其四个组成的富含半胱氨酸的结构域（CRD）排列成棒状的整体结构，呈现出 DR6 特有的表面斑块，负责其配体的特异性识别。基于结构数据、TNFR 的一般配体结合模式和分子建模实验，我们能够阐明潜在的 DR6-APP 信号复合物的结构特征。
