A Common Property of Amyotrophic Lateral Sclerosis-associated Variants DESTABILIZATION OF THE COPPER/ZINC SUPEROXIDE DISMUTASE ELECTROSTATIC LOOP
A Common Property of Amyotrophic Lateral Sclerosis-associated Variants DESTABILIZATION OF THE COPPER/ZINC SUPEROXIDE DISMUTASE ELECTROSTATIC LOOP
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DOI：
10.1074/jbc.m109.023945
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发表时间：
2009-11-06
影响因子：
4.8
通讯作者：
Agar, Jeffrey N.
中科院分区：
文献类型：
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作者：
Molnar, Kathleen S.;Karabacak, N. Murat;Agar, Jeffrey N.
编码铜/锌超氧化物歧化酶（SOD 1）的基因中至少有119个突变通过未鉴定的毒性功能获得引起肌萎缩侧索硬化症。我们比较了13个孤立的，部分金属化，SOD 1变异酶使用氢氘交换的动力学特性。我们确定了这些家族性肌萎缩侧索硬化症相关的SOD 1变体的共同属性，即影响SOD 1的静电环（环VII）的结构和动态变化。此外，具有严重损害的金属结合亲和力的SOD 1变体对SOD 1的锌结合环（环IV）表现出额外的结构和动态变化。尽管环VII迁移率增加的生物学后果尚未完全了解，但这种共同性质与SOD 1突变通过与其他细胞成分聚集或异常缔合而产生毒性的假设一致。
At least 119 mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis by an unidentified toxic gain of function. We compared the dynamic properties of 13 as-isolated, partially metallated, SOD1 variant enzymes using hydrogen-deuterium exchange. We identified a shared property of these familial amyotrophic lateral sclerosis-related SOD1 variants, namely structural and dynamic change affecting the electrostatic loop (loop VII) of SOD1. Furthermore, SOD1 variants that have severely compromised metal binding affinities demonstrated additional structural and dynamic changes to the zinc-binding loop (loop IV) of SOD1. Although the biological consequences of increased loop VII mobility are not fully understood, this common property is consistent with the hypotheses that SOD1 mutations exert toxicity via aggregation or aberrant association with other cellular constituents.