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Abstract
526-residue FUS functions to self-assemble into reversible droplets/hydrogels, which could be further solidified into pathological fibrils. FUS is intrinsically prone to aggregation, composed of N-terminal low-sequence complexity (LC); RNA-recognition motif (RRM) and C-terminal LC domains. Intriguingly, previous in vivo studies revealed that its RRM is required for manifesting FUS cytotoxicity but the underlying mechanism remains unknown. Here, we characterized solution conformations of FUS and its five differentially dissected fragments, followed by detailed investigations on thermal unfolding, NMR dynamics and self-assembly of RRM. The results decipher: (1) the N- and C-terminal LC domains are intrinsically disordered, while RRM is folded. Intriguingly, well-dispersed HSQC peaks of RRM disappear in the full-length FUS, reminiscent of the previous observation on TDP-43. (2) FUS RRM is characteristic of irreversible unfolding. "Model-free" analysis of NMR relaxation data decodes that RRM has high ps-ns conformational dynamics even over some residues within secondary structure regions. (3) RRM spontaneously self-assembles into amyloid fibrils. Therefore, in addition to the well-established prion-like region, FUS RRM is also prone to self-assembly to form amyloid fibrils. Taken together, FUS RRM appears to play a crucial role in exaggerating the physiological/reversible self-assembly into pathological/irreversible fibrillization, thus contributing to manifestation of FUS cytotoxicity. © 2017 The Author(s).
Keywords
amyloid, FUS protein, human, RNA binding protein FUS, amyotrophic lateral sclerosis, chemistry, human, metabolism, nuclear magnetic resonance spectroscopy, pathophysiology, protein conformation, protein domain, protein folding, protein motif, protein multimerization, Amino Acid Motifs, Amyloid, Amyotrophic Lateral Sclerosis, Humans, Magnetic Resonance Spectroscopy, Protein Conformation, Protein Domains, Protein Folding, Protein Multimerization, RNA-Binding Protein FUS
Source Title
Scientific Reports
Publisher
Series/Report No.
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Date
2017
DOI
10.1038/s41598-017-01281-7
Type
Article