Dual function of cysteine rich domain (CRD) 1 of TNF receptor type 1: Conformational stabilization of CRD2 and control of receptor responsiveness
Dual function of cysteine rich domain (CRD) 1 of TNF receptor type 1: Conformational stabilization of CRD2 and control of receptor responsiveness
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DOI：
10.1016/j.cellsig.2009.10.011
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发表时间：
2010-03-01
影响因子：
4.8
通讯作者：
Scheurich, Peter
中科院分区：
文献类型：
--
作者：
Branschaedel, Marcus;Aird, Andrew;Scheurich, Peter
促炎细胞因子肿瘤坏死因子 (TNF) 以同源三聚体形式存在，能够结合三个受体分子。然而，信号活性配体/受体复合物形成大簇，可能通过额外的分子相互作用来稳定。 TNFR1 和 TNFR2 两种 TNF 受体的胞外部分均含有四个富含半胱氨酸的结构域 (CRD)。先前的工作表明膜远端 CRD1 携带同质相互作用结构域。在这里，我们研究了 CRD1 及其两个子模块 A1(CRD1) 和 B2(CRD1) 在 TNFR1-Fas 嵌合体模型系统中的功能作用。去除 CRD1 会消除 TNF 结合。根据这些数据，分子动力学模拟表明 TNFR1 的 B2CRD1 作为支架，将 CRD2 稳定在高亲和力配体结合所需的构象中。仅删除 TNFR1 的 CRD1 N 端一半 (Delta A1(CRD1)) 对配体结合产生轻微影响，但会消除对可溶性 TNF 的反应性，并降低作为野生型 TNFR1 的显性失活抑制剂的有效性。含有来自 TNFR2 的 CRD1 的 TNFR1 衍生分子也显示出对可溶性 TNF 的反应性降低。这些数据强烈表明，CRD1不仅关键参与未连接受体的多聚化，而且还直接参与信号活性配体/受体簇的形成，从而控制受体反应性。 (C) 2009 Elsevier Inc. 保留所有权利。
The proinflammatory cytokine Tumor Necrosis Factor (TNF) exists as a homotrimer, capable of binding three receptor molecules. However, signal competent ligand/receptor complexes form large clusters, likely to be stabilized by additional molecular interactions. Both TNF receptors, TNFR1 and TNFR2, contain four cysteine rich domains (CRD) in their extracellular parts. Previous work showed that the membrane distal CRD1 carries a homophilic interaction domain. Here, we investigated the functional role of CRD1 and its two submodules, A1(CRD1) and B2(CRD1), in a TNFR1-Fas chimera model system. Removal of CRD1 abolishes TNF binding. In line with these data, molecular dynamics simulations suggest that B2CRD1 of TNFR1 serves as a scaffold to stabilize CRD2 in a conformation necessary for high affinity ligand binding. Deletion of only the N-terminal half of CRD1 (Delta A1(CRD1)) of TNFR1 marginally affects ligand binding but abrogates responsiveness towards soluble TNF and reduces effectiveness as a dominant negative inhibitor of wild type TNFR1. A TNFR1-derived molecule containing the CRD1 from TNFR2 also shows reduced responsiveness to soluble TNF. These data strongly suggest that CRD1 is not only crucially involved in multimerization of unligated receptors, but is also directly involved in formation of signal competent ligand/receptor clusters, thereby controlling receptor responsiveness. (C) 2009 Elsevier Inc. All rights reserved.