Oxidation of the Tryptophan 32 Residue of Human Superoxide Dismutase 1 Caused by Its Bicarbonate-dependent Peroxidase Activity Triggers the Non-amyloid Aggregation of the Enzyme
Oxidation of the Tryptophan 32 Residue of Human Superoxide Dismutase 1 Caused by Its Bicarbonate-dependent Peroxidase Activity Triggers the Non-amyloid Aggregation of the Enzyme
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DOI：
10.1074/jbc.m114.586370
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发表时间：
2014-10-31
影响因子：
4.8
通讯作者：
Augusto, Ohara
中科院分区：
文献类型：
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作者：
Coelho, Fernando R.;Iqbal, Asif;Augusto, Ohara
人超氧化物歧化酶1（hSOD 1）的氧化翻译后修饰在肌萎缩侧索硬化症（ALS）病理学中的作用是一个有吸引力的假说，基于几条证据进行探索。其中，显着的稳定性hSOD 1（WT）和它的几个ALS相关的突变体表明，hSOD 1氧化可能先于其转化为未折叠和聚集的形式在ALS患者中发现。hSOD 1的碳酸氢盐依赖性过氧化物酶活性导致其自身暴露于溶剂的Trp（32）残基氧化。所得产物明显不同于在不存在碳酸氢盐的情况下产生的产物，并且最有可能对含有Trp（32）残基的猿猴SOD 1具有特异性。这项工作的目的是检查hSOD 1（hSOD 1 WT和hSOD 1（G93 A）突变体）的碳酸氢盐依赖性过氧化物酶活性是否触发酶的聚集，并了解Trp（32）残基在该过程中的作用。结果表明，这两种酶的Trp（32）残基被氧化到类似的程度，hSOD 1衍生的乙酰基自由基。这些自由基衰变为hSOD 1-N-甲酰犬尿氨酸和hSOD 1-犬尿氨酸或通过双色氨酸键交联的hSOD 1共价二聚体，导致hSOD 1解折叠、寡聚化和非淀粉样蛋白聚集。后一个过程被tempol抑制，tempol与hSOD 1衍生的乙酰基自由基重组，并且在不存在碳酸氢盐或缺乏Trp（32）残基的酶（牛SOD 1和hSOD 1（W32 F）突变体）的情况下不发生。结果支持hSOD 1-Trp（32）残基的氧化产物，特别是共价二聚体，在触发hSOD 1的非淀粉样蛋白聚集中的作用。
The role of oxidative post-translational modifications of human superoxide dismutase 1 (hSOD1) in the amyotrophic lateral sclerosis (ALS) pathology is an attractive hypothesis to explore based on several lines of evidence. Among them, the remarkable stability of hSOD1(WT) and several of its ALS-associated mutants suggests that hSOD1 oxidation may precede its conversion to the unfolded and aggregated forms found in ALS patients. The bicarbonate-dependent peroxidase activity of hSOD1 causes oxidation of its own solvent-exposed Trp(32) residue. The resulting products are apparently different from those produced in the absence of bicarbonate and are most likely specific for simian SOD1s, which contain the Trp(32) residue. The aims of this work were to examine whether the bicarbonate-dependent peroxidase activity of hSOD1 ( hSOD1WT and hSOD1(G93A) mutant) triggers aggregation of the enzyme and to comprehend the role of the Trp(32) residue in the process. The results showed that Trp(32) residues of both enzymes are oxidized to a similar extent to hSOD1-derived tryptophanyl radicals. These radicals decayed to hSOD1-N-formylkynurenine and hSOD1-kynurenine or to a hSOD1 covalent dimer cross-linked by a ditryptophan bond, causing hSOD1 unfolding, oligomerization, and non-amyloid aggregation. The latter process was inhibited by tempol, which recombines with the hSOD1-derived tryptophanyl radical, and did not occur in the absence of bicarbonate or with enzymes that lack the Trp(32) residue (bovine SOD1 and hSOD1(W32F) mutant). The results support a role for the oxidation products of the hSOD1-Trp(32) residue, particularly the covalent dimer, in triggering the non-amyloid aggregation of hSOD1.