FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS

• Published in: PloS one Vol. 7; no. 10; p. e47056
• Main Authors: Niu, Chunyan, Zhang, Jiayu, Gao, Feng, Yang, Liuqing, Jia, Minze, Zhu, Haining, Gong, Weimin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.10.2012; Public Library of Science (PLoS)
• Subjects: Affinity; Amino Acid Sequence; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; beta Karyopherins - chemistry; beta Karyopherins - genetics; beta Karyopherins - metabolism; Biology; Comparative analysis; Crystal structure; Development and progression; FUS protein; Genetic aspects; Humans; Laboratories; Localization; Medicine; Microscopy, Confocal; Molecular Sequence Data; Mutants; Mutation; Nuclear transport; Pathology; Protein Binding; Protein Structure, Secondary; Proteins; RNA-Binding Protein FUS - chemistry; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; Sarcoma; Sequence Homology, Amino Acid; Surface Plasmon Resonance; Beijing China; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047056

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.