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DOI | 10.1038/ncomms14055 |
The mutational landscape of a prion-like domain | |
Bolognesi, Benedetta1,2; Faure, Andre J.1; Seuma, Mireia1,2; Schmiedel, Jorn M.1; Gaetano Tartaglia, Gian1,3,4,5; Lehner, Ben1,3,4 | |
2019-09-13 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2019 |
卷号 | 10 |
文章类型 | Article |
语种 | 英语 |
国家 | Spain; Italy |
英文摘要 | Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000485685900001 |
WOS关键词 | AMYOTROPHIC-LATERAL-SCLEROSIS ; AMYLOID CASCADE HYPOTHESIS ; ABERRANT PHASE-TRANSITIONS ; MISFOLDED PROTEINS ; ALZHEIMERS-DISEASE ; TDP-43 MUTATIONS ; LINKED TDP-43 ; ALS ; AGGREGATION ; RNA |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203159 |
专题 | 资源环境科学 |
作者单位 | 1.Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Doctor Aiguader 88, Barcelona 08003, Spain; 2.Barcelona Inst Sci & Technol, Inst Bioengn Catalonia IBEC, Barcelona, Spain; 3.UPF, Barcelona, Spain; 4.ICREA, Passeig Lluis Co 23, Barcelona 08010, Spain; 5.Sapienza Univ Rome, Dept Biol Charles Darwin, Ple A Moro 5, I-00185 Rome, Italy |
推荐引用方式 GB/T 7714 | Bolognesi, Benedetta,Faure, Andre J.,Seuma, Mireia,et al. The mutational landscape of a prion-like domain[J]. NATURE COMMUNICATIONS,2019,10. |
APA | Bolognesi, Benedetta,Faure, Andre J.,Seuma, Mireia,Schmiedel, Jorn M.,Gaetano Tartaglia, Gian,&Lehner, Ben.(2019).The mutational landscape of a prion-like domain.NATURE COMMUNICATIONS,10. |
MLA | Bolognesi, Benedetta,et al."The mutational landscape of a prion-like domain".NATURE COMMUNICATIONS 10(2019). |
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