RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils

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....

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Autores principales:	Yimei Lu, Liangzhong Lim, Jianxing Song
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac31ba6d3f1f4c03806bbf71a176ee51
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spelling	oai:doaj.org-article:ac31ba6d3f1f4c03806bbf71a176ee512021-12-02T12:30:19ZRRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils10.1038/s41598-017-01281-72045-2322https://doaj.org/article/ac31ba6d3f1f4c03806bbf71a176ee512017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01281-7https://doaj.org/toc/2045-2322Abstract 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.Yimei LuLiangzhong LimJianxing SongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yimei Lu Liangzhong Lim Jianxing Song RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
description	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.
format	article
author	Yimei Lu Liangzhong Lim Jianxing Song
author_facet	Yimei Lu Liangzhong Lim Jianxing Song
author_sort	Yimei Lu
title	RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
title_short	RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
title_full	RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
title_fullStr	RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
title_full_unstemmed	RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
title_sort	rrm domain of als/ftd-causing fus characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ac31ba6d3f1f4c03806bbf71a176ee51
work_keys_str_mv	AT yimeilu rrmdomainofalsftdcausingfuscharacteristicofirreversibleunfoldingspontaneouslyselfassemblesintoamyloidfibrils AT liangzhonglim rrmdomainofalsftdcausingfuscharacteristicofirreversibleunfoldingspontaneouslyselfassemblesintoamyloidfibrils AT jianxingsong rrmdomainofalsftdcausingfuscharacteristicofirreversibleunfoldingspontaneouslyselfassemblesintoamyloidfibrils
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RRM domain of ALS/FTD-causing FUS characteristic of irreversible unfolding spontaneously self-assembles into amyloid fibrils

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