Structural Consequences of ALS-related Modifications of SOD1

摘要： 编码Cu/Zn超氧化物歧化酶的基因中至少有119个突变与肌萎缩相关 侧索硬化这些SOD 1突变被认为导致毒性性质，尽管这种性质是不确定的。 毒性尚未确定。在初步研究中，我们比较了13个 使用氢/氘交换质谱法纯化SOD 1变体酶，并鉴定了一种 共享属性，即影响SOD 1静电回路的结构和动态变化。我们 假设SOD 1的其它修饰，包括天然和非天然翻译后修饰， 也扰乱了SOD 1静电环，并将使用氢/氘交换来检验这一假设 质谱分析法来虽然静电环迁移率增加的生物学后果并不完全清楚， 理解，这一共同性质将与SOD 1突变通过以下途径发挥毒性的假设一致： 与其他细胞成分的聚集或异常结合。

Abstract: At least 119 mutations in the gene encoding Cu/Zn superoxide dismutase are associated with amyotrophic lateral sclerosis. These SOD1 mutations are believed to result in a toxic property, although the nature of this toxic property has not been identified. In preliminary studies we compared the dynamic properties of thirteen purified SOD1 variant enzymes using hydrogen/deuterium exchange mass spectrometry and identified a shared property, namely structural and dynamic change affecting the electrostatic loop of SOD1. We hypothesize that other modifications of SOD1, including native and non-native post-translational modifications, also perturb the SOD1 electrostatic loop and will test this hypothesis using hydrogen/deuterium exchange mass spectrometry. Although the biological consequences of increased electrostatic loop mobility are not fully understood, this common property would be consistent with hypotheses that SOD1 mutations exert toxicity via aggregation or aberrant association with other cellular constituents.