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

被引:31
作者
Agrawal, Sashank [1 ,2 ,3 ]
Kuo, Pan-Hsien [3 ]
Chu, Lee-Ya [3 ,4 ,5 ]
Golzarroshan, Bagher [3 ]
Jain, Monika [1 ,2 ,3 ]
Yuan, Hanna S. [1 ,2 ,3 ]
机构
[1] Acad Sinica, Taiwan Int Grad Program, Mol & Cell Biol, Taipei, Taiwan
[2] Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan
[3] Acad Sinica, Inst Mol Biol, Taipei, Taiwan
[4] Acad Sinica, Taiwan Int Grad Program, Chem Biol & Mol Biophys, Taipei, Taiwan
[5] Natl Tsing Hua Univ, Inst Bioinformat & Struct Biol, Hsinchu, Taiwan
关键词
FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; RAY FIBER DIFFRACTION; TDP-43; PROTEINOPATHY; CRYSTAL-STRUCTURE; NEURONAL INCLUSIONS; PHASE-SEPARATION; ATR-FTIR; FTLD-TDP; 45; RBM45;
D O I
10.1038/s41598-019-42367-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-peptides from these two RRMs, could self-assemble into fibril-like aggregates which are amyloids of parallel beta-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.
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页数:12
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