RNA recognition motifs of disease-linked RNA-binding proteins contribute to amyloid formation

• Published in: Scientific reports 2019-04, Vol.9 (1), p.6171-6171, Article 6171
• Main Authors: Agrawal, Sashank, Kuo, Pan-Hsien, Chu, Lee-Ya, Golzarroshan, Bagher, Jain, Monika, Yuan, Hanna S.
• Format: Article
• Language: English
• Subjects: 631/45/470/2284; 631/57/2272/2273; 82/16; 82/83; Amyloid; Amyloid - chemistry; Amyloid - metabolism; Amyloid - ultrastructure; Disease; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Humanities and Social Sciences; Humans; Infrared spectroscopy; multidisciplinary; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Neurological diseases; Protein Aggregates; Protein Unfolding; Proteins; Ribonucleic acid; RNA; RNA Recognition Motif; RNA-binding protein; RNA-Binding Protein FUS - chemistry; RNA-Binding Protein FUS - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Self-assembly; Temperature; X-ray diffraction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42367-8

Aberrant expression, dysfunction and particularly aggregation of a group of RNA-binding proteins, including TDP-43, FUS and RBM45, are associated with neurological disorders. These three disease-linked RNA-binding proteins all contain at least one RNA recognition motif (RRM). However, it is not clear if these RRMs contribute to their aggregation-prone character. Here, we compare the biophysical and fibril formation properties of five RRMs from disease-linked RNA-binding proteins and five RRMs from non-disease-associated proteins to determine if disease-linked RRMs share specific features making them prone to self-assembly. We found that most of the disease-linked RRMs exhibit reversible thermal unfolding and refolding, and have a slightly lower average thermal melting point compared to that of normal RRMs. The full domain of TDP-43 RRM1 and FUS RRM, as well as the β-peptides from these two RRMs, could self-assemble into fibril-like aggregates which are amyloids of parallel β-sheets as verified by X-ray diffraction and FT-IR spectroscopy. Our results suggest that some disease-linked RRMs indeed play important roles in amyloid formation and shed light on why RNA-binding proteins with RRMs are frequently identified in the cellular inclusions of neurodegenerative diseases.