Molnar Kathleen S, Karabacak N Murat, Johnson Joshua L, Wang Qi, Tiwari Ashutosh, Hayward Lawrence J, Coales Stephen J, Hamuro Yoshitomo, Agar Jeffrey N
Department of Chemistry, Volen Center, Brandeis University, Waltham, Massachusetts 02454, USA.
J Biol Chem. 2009 Nov 6;284(45):30965-73. doi: 10.1074/jbc.M109.023945. Epub 2009 Jul 27.
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.
编码铜/锌超氧化物歧化酶（SOD1）的基因中至少119种突变通过未知的毒性功能获得导致肌萎缩侧索硬化症。我们使用氢-氘交换比较了13种刚分离出来的、部分金属化的SOD1变体酶的动力学特性。我们确定了这些与家族性肌萎缩侧索硬化症相关的SOD1变体的一个共同特性，即影响SOD1静电环（环VII）的结构和动力学变化。此外，金属结合亲和力严重受损的SOD1变体在SOD1的锌结合环（环IV）上表现出额外的结构和动力学变化。虽然环VII流动性增加的生物学后果尚未完全了解，但这一共同特性与SOD1突变通过聚集或与其他细胞成分异常结合发挥毒性的假设一致。
