Structural Basis for the Antiproliferative Activity of the Tob-hCaf1 Complex
Structural Basis for the Antiproliferative Activity of the Tob-hCaf1 Complex
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DOI：
10.1074/jbc.m809250200
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发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Inagaki, Fuyuhiko
中科院分区：
文献类型：
--
作者：
Horiuchi, Masataka;Takeuchi, Kosei;Inagaki, Fuyuhiko
ToB/BTG家族是一组抗增殖蛋白，包含两个高度同源的区域，盒A和盒B。这些蛋白质都与CCR 4相关因子1（Caf 1）相关，Caf 1属于核糖核酸酶D（RNase D）脱氧腺苷酶家族，是CCR 4-Not脱氧腺苷酶复合物的组分。在这里，我们确定了Tob和人Caf 1（hCaf 1）的N-末端区域的复合物的晶体结构。Tob表现出一种新的折叠，而hCaf 1最接近的酵母Pop 2和人类poly（A）特异性核糖核酸酶的催化结构域。有趣的是，hCaf 1的结合由ToB的盒A和盒B介导。使用野生型和突变蛋白的细胞生长测定显示，去腺苷酶活性的Caf 1是不重要的，但复合物的形成是至关重要的细胞生长抑制。Caf 1将Tob与CCR 4-Not去腺苷酶复合物连接，从而Tob在其C-末端区域聚集几种因子，如poly（A）结合蛋白，以发挥抗增殖活性。
The Tob/BTG family is a group of antiproliferative proteins containing two highly homologous regions, Box A and Box B. These proteins all associate with CCR4-associated factor 1 (Caf1), which belongs to the ribonuclease D (RNase D) family of deadenylases and is a component of the CCR4-Not deadenylase complex. Here we determined the crystal structure of the complex of the N-terminal region of Tob and human Caf1 (hCaf1). Tob exhibited a novel fold, whereas hCaf1 most closely resembled the catalytic domain of yeast Pop2 and human poly(A)-specific ribonuclease. Interestingly, the association of hCaf1 was mediated by both Box A and Box B of Tob. Cell growth assays using both wild-type and mutant proteins revealed that deadenylase activity of Caf1 is not critical but complex formation is crucial to cell growth inhibition. Caf1 tethers Tob to the CCR4-Not deadenylase complex, and thereby Tob gathers several factors at its C-terminal region, such as poly(A)-binding proteins, to exert antiproliferative activity.