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DOI | 10.1038/s41467-018-06683-3 |
A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers | |
Thibaudeau, Tiffany A.; Anderson, Raymond T.; Smith, David M. | |
2018-03-15 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000427470600008 |
WOS关键词 | AMYLOID-BETA-PROTEIN ; 20S PROTEASOME ; 26S PROTEASOME ; MUTANT HUNTINGTIN ; INCLUSION-BODIES ; UBIQUITIN ; DEGRADATION ; SYSTEM ; INHIBITION ; BRAIN |
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/204037 |
专题 | 资源环境科学 |
作者单位 | West Virginia Univ, Sch Med, Dept Biochem, POB 9142, Morgantown, WV 26501 USA |
推荐引用方式 GB/T 7714 | Thibaudeau, Tiffany A.,Anderson, Raymond T.,Smith, David M.. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Thibaudeau, Tiffany A.,Anderson, Raymond T.,&Smith, David M..(2018).A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers.NATURE COMMUNICATIONS,9. |
MLA | Thibaudeau, Tiffany A.,et al."A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers".NATURE COMMUNICATIONS 9(2018). |
条目包含的文件 | 条目无相关文件。 |
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