Structural Consequences of ALS-related Modifications of SOD1

摘要： 至少119个铜/锌超氧化物歧化酶基因突变与肌萎缩症有关 侧索硬化症。这些SOD1突变被认为会导致一种有毒的性质，尽管这种性质 有毒物质的性质尚未确定。在初步研究中，我们比较了13个 氢/氚交换质谱法纯化SOD1变异体酶鉴定 共享性，即影响SOD1静电回路的结构和动态变化。我们 假设SOD1的其他修改，包括原生和非原生翻译后修饰， 也扰乱了SOD1静电回路，并将使用氢/氢交换来测试这一假设 质谱学。尽管增加静电环迁移率的生物学后果并不完全 理解，这一共同属性将与SOD1突变通过以下途径产生毒性的假设一致 与其他细胞成分聚集或异常结合。

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.