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 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 (K(D) = 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.
Document Type
Article
Publication Date
10-8-2012
Digital Object Identifier (DOI)
http://dx.doi.org/10.1371/journal.pone.0047056
Repository Citation
Niu, Chunyan; Zhang, Jiayu; Gao, Feng; Yang, Liuqing; Jia, Minze; Zhu, Haining; and Gong, Weimin, "FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS" (2012). Molecular and Cellular Biochemistry Faculty Publications. 9.
https://uknowledge.uky.edu/biochem_facpub/9
Supporting documents
Notes/Citation Information
Published in PLoS ONE, v. 7, no. 10, e47056.
© Niu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.