Crystal structure of the human TβR2 ectodomain-TGF-β3 complex
Crystal structure of the human TβR2 ectodomain-TGF-β3 complex
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DOI：
10.1038/nsb766
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发表时间：
2002-03-01
期刊：
影响因子：
--
通讯作者：
Hinck, AP
中科院分区：
文献类型：
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作者：
Hart, PJ;Deep, S;Hinck, AP
转化生长因子-β（TGF-β）是结构上相关的细胞因子的大家族的原型，其通过经由两类功能上不同的Ser/Thr激酶受体（指定为I型和II型）的信号传导在维持细胞稳态中发挥关键作用。TGF-β通过与II型受体高亲和力结合来启动受体组装。在这里，我们提出了2.15埃的晶体结构的胞外配体结合域的人TGF-β II型受体（ECTbetaR 2）与人TGF-β 3的复合物。ECTbetaR 2通过在生长因子的相对末端结合相同的指状片段与同源二聚体TGF-β 3相互作用。相对于先前在超家族的配体结构中观察到的典型“闭合”构象，ECTbetaR 2结合的TGF-β 3显示其单体亚基的改变的排列，称为“开放”构象。ECTbetaR 2所示的TGF-β 3结合模式与两种配体构象相容。除了预测的TGF-β与I型受体胞外域（ectTbetaR 1）结合的模式外，这表明了一种组装机制，其中ectTbetaR 1和ectTbetaR 2在配体表面的相邻位置结合，并通过蛋白质-蛋白质相互作用直接相互接触。
Transforming growth factor-beta (TGF-beta) is the prototype of a large family of structurally related cytokines that play key roles in maintaining cellular homeostasis by signaling through two classes of functionally distinct Ser/Thr kinase receptors, designated as type I and type II. TGF-beta initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 Angstrom crystal structure of the extracellular ligand-binding domain of the human TGF-beta type II receptor (ecTbetaR2) in complex with human TGF-beta3. ecTbetaR2 interacts with homodimeric TGF-beta3 by binding identical finger segments at opposite ends of the growth factor. Relative to the canonical 'closed' conformation previously observed in ligand structures across the superfamily, ecTbetaR2-bound TGF-beta3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-beta3 binding shown by ecTbetaR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-beta binding to the type I receptor ectodomain (ecTbetaR1), suggests an assembly mechanism in which ecTbetaR1 and ecTbetaR2 bind at adjacent positions on the ligand surface and directly contact each other via protein-protein interactions.