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hnRNPA2低复杂性域的D290V突变体的冷EM结构表明D290V如何影响相位分离和聚合

Jiahui Lu¹, Peng Ge¹, Michael R Sawaya¹

¹Departments of Chemistry and Biochemistry and Biological Chemistry, University of California, Los Angeles, Los Angeles, California, USA; UCLA-DOE Institute, Molecular Biology Institute, Howard Hughes Medical Institute, Los Angeles, California, USA.

The Journal of biological chemistry

|December 10, 2023

概括

突变的hnnRNPA2蛋白 (D290V) 形成比野生类型更稳定的粉样纤维,这可能解释了它在多系统蛋白质病变和相关神经疾病中的作用.

科学领域:

生物化学生化学
结构生物学结构生物学
分子生物学分子生物学

背景情况:

异质核核核糖核蛋白A2 (hnRNPA2) 对于RNA传输和相分离至关重要.
突变的hnRNPA2 (D290V) 与多系统蛋白质病变有关,包括肌肉病变和帕杰特病.
了解 hnRNPA2 突变的结构基础是解读相关疾病的关键.

研究的目的:

为了确定 hnRNPA2 D290V 突变低复杂性域的冷EM结构.
阐明野生类型 (WT) 和突变hnnRNPA2纤维之间的结构差异.
解释D290V突变将功能纤维转化为致病性粉样蛋白.

主要方法:

电子显微镜 (cryo-EM) 用于确定纤维结构.
阶段分离测试,热稳定性测试和能量计算.
野生类型和D290V突变hnnRNPA2纤维的结构比较.

主要成果:

突变D290V的hNRNPA2形成了与WT纤维不同的多态纤维.
突变纤维细胞核中的PY核定位信号对陪伴者来说难以获得.
与WT纤维相比,突变的hnnRNPA2纤维具有更高的稳定性.

结论:

D290V突变促进了从功能 hnRNPA2 的稳定,致病性粉样纤维的形成.
结构洞察力解释了误解突变如何驱动转化为致病性粉样蛋白.
这些发现可能会揭示与核糖蛋白相关的神经障碍 (如ALS和FTD) 背后的机制.

关键词:

阿尔茨海默病的疾病阿尔茨海默病的疾病.鱼鱼鱼鱼鱼氨基化物氨基化物凝结剂是一种凝结剂.冰冷化EMEM可以使用.低复杂度的域名域名没有膜的有机细胞.多系统蛋白质病变多系统蛋白质病变核定位信号是一个核定位信号.阶段分离的阶段分离.它是多元形态的.蛋白质聚合蛋白质的聚合物核糖核蛋白 A2 是一种核糖核蛋白.

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