Regulation of Stat3 nuclear import by importin α5 and importin α7 via two different functional sequence elements
Regulation of Stat3 nuclear import by importin α5 and importin α7 via two different functional sequence elements
复制标题
DOI：
10.1016/j.cellsig.2005.06.016
复制
发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Cao, Xinmin
中科院分区：
文献类型：
--
作者：
Ma, Jing;Cao, Xinmin
通过核孔对STAT蛋白进行受调控的核输入是一个至关重要的事件。我们先前鉴定出卷曲螺旋结构域中的Arg214/215以及DNA结合结构域中的Arg414/417参与了配体诱导的Stat3核转位。在本研究中，我们探究了Stat3核转运的机制。在此我们报道，在五种普遍表达的人输入蛋白α中，输入蛋白α5和α3（而非输入蛋白α1、α2和α4）在细胞因子刺激时与Stat3结合。对于Stat1也观察到了类似结果，但对于Stat5a和5b则未观察到，它们无法与任何输入蛋白α相互作用。输入蛋白α5的C末端对于Stat3结合是必要的，但并非充分的。包含Arg214/215的Stat3截短突变体（aa1 - 320）表现出与输入蛋白α5的特异性结合以及专一的核定位。该突变体中Arg214/215的点突变破坏了与输入蛋白α5的结合及其核定位。相反，包含Arg414/417的截短突变体（aa320 - 770）无法与输入蛋白α5相互作用且定位于细胞质。然而，这两个序列元件对于全长Stat3与输入蛋白α5的相互作用都是必需的。这些结果表明，Arg214/215可能是输入蛋白α5的结合位点，而Arg414/417可能不参与直接结合，但对于维持Stat3二聚体适合输入蛋白结合的正确构象是必要的。基于这些数据提出了一个Stat3核转位的模型。（c）2005爱思唯尔公司。保留所有权利。
Regulated import of STAT proteins into the nucleus through the nuclear pores is a vital event. We previously identified Arg214/215 in the coiled-coil domain and Arg414/417 in the DNA binding domain involved in the ligand-induced nuclear translocation of Stat3. In this study, we investigated the mechanism for Stat3 nuclear transport. We report here that among five ubiquitously expressed human importin alpha s, importin alpha 5 and 0, but not importin a 1, 0, and alpha 4, bind to Stat3 upon cytokine stimulation. Similar results were observed for Stat1, but not for Stat5a and 5b, which were unable to interact with any of the importin us. The C-terminus of importin alpha 5 is necessary but not sufficient for Stat3 binding. Truncation mutant of Stat3 (aa1-320) that contains Arg214/215 exhibits specific binding to importin alpha 5, and an exclusive nuclear localization. Point mutations of Arg214/215 in this mutant destroy importin a5 binding and its nuclear localization. In contrast, the truncation mutant (aa320-770) including Arg414/417 fails to interact with importin alpha 5 and is localized in the cytoplasm. However, both sequence elements are necessary for the full-length Stat3's interaction with importin alpha 5. These results suggest that Arg214/215 is likely the binding site for importin alpha 5, whereas Arg414/417 may not be involved in the direct binding, but necessary for maintaining the proper conformation of Stat3 dimer for importin binding. A model for Stat3 nuclear translocation is proposed based on these data. (c) 2005 Elsevier Inc. All rights reserved.