Cryo-EM structure of the full-length hnRNPA1 amyloid fibril.
Cryo-EM structure of the full-length hnRNPA1 amyloid fibril.
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DOI：
10.1016/j.jmb.2023.168211
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发表时间：
2023-07
影响因子：
5.6
通讯作者：
Kartikay Sharma;Sambhasan Banerjee;Dilan Savran;Cedric Rajes;S. Wiese;A. Girdhar;N. Schwierz;
中科院分区：
文献类型：
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作者：
Kartikay Sharma;Sambhasan Banerjee;Dilan Savran;Cedric Rajes;S. Wiese;A. Girdhar;N. Schwierz;
异质核核糖核蛋白 A1 (hnRNPA1) 是一种多功能 RNA 结合蛋白，与肌萎缩侧索硬化症和多系统蛋白病等神经退行性疾病相关。在这项研究中，我们使用冷冻电子显微镜研究全长 hnRNPA1 蛋白淀粉样原纤维的三维结构。我们发现原纤维核心是由蛋白质的类朊病毒低复杂性结构域的 45 个残基片段形成的，而蛋白质的其余部分（275 个残基）在原纤维核心周围形成一层模糊的外壳。原纤维由两个原纤维蛋白堆叠组成，排列成伪 21 螺旋对称。有序核心包含多个已知受疾病相关突变影响的位置，但不包含蛋白质中最容易聚集的片段。这些数据表明，全长蛋白质的淀粉样原纤维的结构可能比当前蛋白质错误折叠理论预期的更复杂。
Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-21screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding.