Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS
Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS
复制标题
DOI：
10.1038/nsb935
复制
发表时间：
2003-06-01
期刊：
影响因子：
--
通讯作者：
Hart, PJ
中科院分区：
文献类型：
--
作者：
Elam, JS;Taylor, AB;Hart, PJ
SOD 1基因的突变导致常染色体显性遗传的神经退行性疾病家族性肌萎缩侧索硬化症（FALS）。在人FALS患者的脊髓神经元和表达这些突变蛋白的转基因小鼠中，观察到含有FALSSOD 1的聚集体。SOD 1聚集体的积累被认为干扰神经元细胞机器的轴突运输、蛋白质降解和抗凋亡功能。在这里，我们表明，金属缺乏，致病性SOD 1突变蛋白结晶在三种不同的晶体形式，所有这些都揭示了更高层次的组件对齐β-片。淀粉样纤维和充满水的纳米管通过相邻突变SOD 1分子的环和β-桶元件之间的广泛相互作用而产生。在所有情况下，非天然构象变化允许二聚体之间的相互作用的增益，导致更高阶的阵列。含有正常β折叠的蛋白质通过防止它们的边缘链进行分子间相互作用来避免这种自缔合。这种保护的损失，通过构象重排的金属缺陷的酶可能是一种常见的毒性的突变体的SOD 1连接到FALS。
Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed. Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery. Here we show that metal-deficient, pathogenic SOD1 mutant proteins crystallize in three different crystal forms, all of which reveal higher-order assemblies of aligned beta-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and beta-barrel elements of neighboring mutant SOD1 molecules. In all cases, non-native conformational changes permit a gain of interaction between dimers that leads to higher-order arrays. Normal beta-sheet containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions. Loss of this protection through conformational rearrangement in the metal-deficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.