在ALS和FTD中非充分的C9orf72ARFGAP复合物的结构
Ming-Yuan Su1,2, Simon A Fromm1,2, Roberto Zoncu1,2
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Nature
|August 28, 2020
概括
在C9orf72-SMCR8-WDR41复合体
科学领域:
- 神经科学
- 分子生物学
- 结构生物学
背景情况:
- C9orf72突变是肌缩侧面硬化 (ALS) 和前退行 (FTD) 的主要遗传原因.
- 在这些神经退行性疾病中,Haploinsufficiency和C9orf72的重复扩张会导致神经元功能障碍.
- 在细胞过程中C9orf72的精确分子功能仍然不完全理解.
研究的目的:
- 阐明C9orf72-SMCR8-WDR41复合物的结构基础.
- 调查这个复合体在细胞通路中的功能作用.
- 了解C9orf72功能障碍如何导致神经退行.
主要方法:
- 使用冷电子显微镜确定C9orf72-SMCR8-WDR41复合物的高分辨率结构.
- 使用生物化学测定来评估该复合物的酶活性.
- 在各种条件下进行细胞局部化研究,包括氨基酸饥饿.
主要成果:
- 冷电磁结构显示了一个独特的组合,类似于眼球滑动,WDR41和SMCR8 DENN域之间具有特定的相互作用.
- 在氨基酸饥饿时,C9orf72-SMCR8-WDR41复合物定位到溶酶体,这表明它在营养感知或反应中发挥作用.
- 该复合物被确定为GTPase激活蛋白 (GAP),专门用于小GTPases的ARF家族.
结论:
- C9orf72-SMCR8-WDR41复合体的结构和功能特征为C9orf72在正常细胞生理中的作用提供了关键的见解.
- 这一发现确立了C9orf72作为ARF GTPases的GAP,将其与基本的细胞信号通路联系起来.
- 了解该复合体的功能可能会为C9orf72相关的神经退行性疾病 (如ALS和FTD) 揭示新的治疗点.
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