FUS-NLS/Transportin 1 Complex Structure Provides Insights into the Nuclear Targeting Mechanism of FUS and the Implications in ALS

• DOI: 10.1371/journal.pone.0047056
• Publication Date: 2012-10-08T21:08:15Z
• Authors: Chunyan Niu; Jiayu Zhang; Feng Gao; Liuqing Yang; Minze Jia; Haining Zhu; Weimin Gong
• Keywords: 0303 health sciences; Microscopy, Confocal; Sequence Homology, Amino Acid; Science; Q; Amyotrophic Lateral Sclerosis; Molecular Sequence Data; R; Surface Plasmon Resonance; beta Karyopherins; Protein Structure, Secondary; 03 medical and health sciences; Medicine; Humans; RNA-Binding Protein FUS; Amino Acid Sequence; Research Article; Protein Binding

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.