Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis
Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis
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DOI：
10.1007/s100480050010
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发表时间：
1997-05-01
期刊：
影响因子：
2.2
通讯作者：
Siddique, T
中科院分区：
文献类型：
--
作者：
Zu, JS;Deng, HX;Siddique, T
在家族性肌萎缩侧索硬化症（familial amyotrophic lateral sclerosis，FALS）患者的胞浆铜锌超氧化物歧化酶（Cu，Zn superoxide dismutase，SOD 1）基因中发现了两个新的突变，导致外显子5编码的大部分多肽片段被截短，一个是在密码子126处形成终止密码子（L126 Z），另一个是在mRNA中诱导选择性剪接（splicing junction mutation）。SOD 1的这两种突变体导致与在SOD 1基因中具有错义突变的患者中观察到的表型相似的FALS表型，确立了与ALS相关的突变体SOD 1的新毒性功能不需要外显子5。这些突变体酶在FALS患者中以非常低的水平存在，表明与具有单位点取代的突变体酶相比毒性升高。这种增加的毒性可能是由突变酶中观察到的活性位点通道、β-桶折叠和二聚体界面的极端结构和功能变化引起的，包括天然歧化酶活性的丧失。特别是，多肽链的截短显著地打开了活性位点通道，导致酶活性位点的金属离子和侧链配体的可及性和灵活性显著增加。提出这些结构变化导致底物特异性降低和有害化学反应的催化增加，例如过氧化催化。
Two new mutations in the gene encoding cytoplasmic Cu,Zn superoxide dismutase (SOD1) have been discovered inpatients with familial amyotrophic lateral sclerosis (FALS), These mutations result in the truncation of most of the polypeptide segment encoded by exon 5, one by the formation of a stop codon in codon 126 (L126Z) and the other by inducing alternative splicing in the mRNA (splicing junction mutation). These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS, These mutant enzymes are present at very low levels in FALS patients, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity likely arises from the extreme structural and functional changes in the active site channel, beta-barrel fold, and dimer interface observed in the mutant enzymes, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the enzyme active site. These structural changes are proposed to cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as catalysis of peroxidation.