Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding
Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding
复制标题
锌超氧化物歧化酶通过异常铜结合诱导氧化应激
DOI：
10.1016/j.freeradbiomed.2010.01.008
复制
发表时间：
2010
影响因子：
7.4
通讯作者：
Sakoda S. Monomerized Cu
中科院分区：
文献类型：
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作者：
Kishigami H;Nagano S;Bush AI;Sakoda S. Monomerized Cu
铜锌超氧化物歧化酶（SOD 1）基因突变导致家族性肌萎缩侧索硬化症（FALS）。降低细胞内铜改善突变型SOD 1小鼠的CNS样表型使用固定化铜亲和层析，我们以前已经表明，突变体SOD 1表达为两个亲和部分，一个具有高亲和力的铜（SOD 1HAC）和一个具有低亲和力（SOD 1 LAC），而野生型SOD 1只表达为SOD 1 LAC。在这里，我们进一步表征SOD 1HACto确定突变的SOD 1物种的毒性。我们发现SOD 1HACs在半胱氨酸残基（Cys）处被修饰，并且可以通过氧化Cys从野生型SOD 1产生。SOD 1 TAC主要由单体组成，而SOD 1 LAC为二聚体。突变体SOD 1 s具有异位硫醇氧化酶活性，通过加载外膜铜夸大，但这种活性在野生型SOD 1中是最小的。野生型SOD 1可通过Cys的氧化而被诱导产生活性。相反，突变体SOD 1通过用交联剂迫使其脱离单体状态而降低活性。一个显着减少游离巯基浓度观察到在Neuro 2a细胞转染突变SOD 1 s时，他们与铜处理。SOD 1HACs作为一种单体物质，通过与Cu ~（2+）的异常配位而获得氧化还原活性，可能是FALS的致病因素。
Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Lowering intracellular Cu improves the FALS-like phenotype of mutant SOD1 mice. Using immobilized Cu-affinity chromatography, we have previously shown that mutant SOD1 is expressed as two affinity fractions, one with high affinity for Cu (SOD1HAC) and one with low affinity (SOD1LAC), whereas wild-type SOD1 is expressed only as SOD1LAC. Here we further characterize SOD1HACto ascertain the toxicity of mutant SOD1 species. We found that SOD1HACwas modified at cysteine residues (Cys) and could be generated from wild-type SOD1 by oxidation of Cys. SOD1HACmainly consisted of monomer, whereas SOD1LACwas a dimer. Mutant SOD1s possessed ectopic thiol oxidase activity that was exaggerated by loading it with adventitial Cu, but this activity was minimal in wild-type SOD1. Wild-type SOD1 could be induced to develop the activity by oxidation of Cys. Conversely, mutant SOD1 decreased the activity by being forced away from its monomeric state with a cross-linker. A significant decrease in free thiol concentration was observed in Neuro2a cells transfected with mutant SOD1s when they were treated with Cu. SOD1HACmay be pathogenic in FALS by being a monomeric species that gains a redox activity by aberrantly coordinating Cu2+.