fus-nlstransportin 1 complex structure provides insights into the nuclear targeting mechanism of fus and the implications in alsfus-nlstransportin 1复杂结构提供了洞察付的核目标机制和als的影响.pdfVIP

fus-nlstransportin 1 complex structure provides insights into the nuclear targeting mechanism of fus and the implications in alsfus-nlstransportin 1复杂结构提供了洞察付的核目标机制和als的影响.pdf

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fus-nlstransportin 1 complex structure provides insights into the nuclear targeting mechanism of fus and the implications in alsfus-nlstransportin 1复杂结构提供了洞察付的核目标机制和als的影响

FUS-NLS/Transportin 1 Complex Structure Provides Insights into the Nuclear Targeting Mechanism of FUS and the Implications in ALS 1. 2. 1. 2 1 2 1 Chunyan Niu , Jiayu Zhang , Feng Gao , Liuqing Yang , Minze Jia , Haining Zhu *, Weimin Gong * 1 Laboratory of Non-coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China, 2 Department of Molecular and Cellular Biochemistry Center for Structural Biology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America Abstract 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 a-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. Citation: Niu C, Zhang J, Gao F, Yang L, Jia M, et al. (2012) FUS-NLS/Transportin 1 Complex Structure Provides

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