FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS.
FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS.
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FUS-NLS/Transportin 1 复杂结构深入了解 FUS 的核靶向机制及其对 ALS 的影响
DOI：
10.1371/journal.pone.0047056
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gong W
中科院分区：
文献类型：
--
作者：
Niu C;Zhang J;Gao F;Yang L;Jia M;Zhu H;Gong W
肉瘤融合蛋白（FUS-NLS）的C端核定位序列是其通过转运蛋白（Trn 1）介导的核输入的关键。家族性肌萎缩侧索硬化症（ALS）相关突变在FUS-NLS中聚集。我们在这里报告的结构，生化和细胞生物学特性的FUS-NLS及其临床意义。FUS-NLS/Trn 1复合物的晶体结构显示了两种蛋白质之间的广泛接触和FUS-NLS中独特的α-螺旋结构。测定Trn 1和FUS-NLS（野生型和12种ALS相关突变体）之间的结合亲和力。与野生型FUS-NLS（KD = 1.7 nM）相比，每个ALS相关突变引起亲和力降低，并且这种降低的范围从1.4倍到700倍变化很大。 突变体的亲和力与核定位受损的程度相关，更重要的是，与ALS患者疾病进展的持续时间相关。本研究为FUS的核靶向机制提供了全面的理解，并阐明了FUS-NLS在ALS中的意义。
The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1). Familial amyotrophic lateral sclerosis (ALS) related mutations are clustered in FUS-NLS. We report here the structural, biochemical and cell biological characterization of the FUS-NLS and its clinical implications. The crystal structure of the FUS-NLS/Trn1 complex shows extensive contacts between the two proteins and a unique α-helical structure in the FUS-NLS. The binding affinity between Trn1 and FUS-NLS (wide-type and 12 ALS-associated mutants) was determined. As compared to the wide-type FUS-NLS (KD = 1.7 nM), each ALS-associated mutation caused a decreased affinity and the range of this reduction varied widely from 1.4-fold over 700-fold. The affinity of the mutants correlated with the extent of impaired nuclear localization, and more importantly, with the duration of disease progression in ALS patients. This study provides a comprehensive understanding of the nuclear targeting mechanism of FUS and illustrates the significance of FUS-NLS in ALS.
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影响因子：
4.2
作者：
Gal J;Zhang J;Kwinter DM;Zhai J;Jia H;Jia J;Zhu H
通讯作者：
Zhu H
影响因子：
4.2
作者：
Chio, Adriano;Restagno, Gabriella;Brunetti, Maura;Ossola, Irene;Calvo, Andrea;Mora, Gabriele;Sabatelli, Mario;Monsurro, Maria Rosaria;Battistini, Stefania;Mandrioli, Jessica;Salvi, Fabrizio;Spataro, Rossella;Schymick, Jennifer;Traynor, Bryan J.;La Bella, Vincenzo
通讯作者：
La Bella, Vincenzo
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
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：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH