Structural basis for nuclear import selectivity of pioneer transcription factor SOX2.
Structural basis for nuclear import selectivity of pioneer transcription factor SOX2.
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DOI：
10.1038/s41467-020-20194-0
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发表时间：
2021-01-04
影响因子：
16.6
通讯作者：
Forwood JK
中科院分区：
文献类型：
--
作者：
Jagga B;Edwards M;Pagin M;Wagstaff KM;Aragão D;Roman N;Nanson JD;Raidal SR;Dominado N;Stewart M;Jans DA;Hime GR;Nicolis SK;Basler CF;Forwood JK
SOX （sry相关的HMG-box）转录因子在发育和细胞分化中发挥关键作用。这些作用取决于精确的核转运，核靶向区域的突变导致发育性疾病和一系列癌症。SOX蛋白核定位被认为是由位于dna结合HMG-box结构域末端的两个核定位信号（NLSs）介导的，尽管其中任何一个区域的突变都会导致疾病，但其机制基础仍不清楚。出乎意料的是，我们发现SOX2的这两个位置遥远的NLSs在核导入适配器IMPα3上形成了一个连续的界面，跨越了10个ARM结构域中的9个。我们确定了关键的结合决定因素，并表明该界面对神经干细胞的维持和果蝇的发育至关重要。此外，我们确定了SOX2偏好与IMPα3结合的结构基础。除了定义SOX蛋白定位的结构基础外，这些结果还为理解这些区域内的突变和翻译后修饰如何调节核定位并导致临床疾病，以及其他含有多个NLSs的蛋白质如何通过扩展的识别接口与IMPα结合提供了平台。SOX2先驱转录因子在胚胎干细胞的多能性和自我更新中起着关键作用。本文作者发现SOX2的两个核定位信号序列在核输入受体importin-α3上形成了一个连续的结合界面，为SOX2倾向于结合IMPα3提供了结构基础。
SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface. The SOX2 pioneer transcription factor performs critical roles in pluripotency and self-renewal of embryonic stem cells. Here the authors show that SOX2’s two nuclear localization signal sequences form a contiguous binding interface on the nuclear import receptor importin-α3, and provide a structural basis for the preference of SOX2 binding to IMPα3.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
影响因子：
4.6
作者：
Cavallaro, Maurizio;Mariani, Jessica;Nicolis, Silvia K.
通讯作者：
Nicolis, Silvia K.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.1300828110
发表时间：
2013-09-17
影响因子：
11.1
作者：
Chen, Yen-Shan;Racca, Joseph D.;Weiss, Michael A.
通讯作者：
Weiss, Michael A.
影响因子：
5.2
作者：
Jethon, Aleksandra;Pula, Bartosz;Podhorska-Okolow, Marzena
通讯作者：
Podhorska-Okolow, Marzena