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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants
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Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants

机译：超氧化物歧化酶中二聚体的不稳定可能导致致病特性：运动神经元疾病突变体的结构

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摘要

More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile1 13Thr (I1 13T) mutants to 1.9 and 1.6 Angstrom, respectively. In the A4V structure, small changes at the dinner interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I1 13T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80degreesC. These results demonstrate that the A4V and I1 13T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.
机译：人类CuZn超氧化物歧化酶中超过90点的突变导致家族性肌萎缩性侧索硬化症的发展，也称为运动神经元疾病。越来越多的证据表明，靠近二聚体界面的突变子集会导致突变酶的严重失稳。我们已经确定了分别为1.9和1.6埃的Ala4Val（A4V）和Ile1 13Thr（I1 13T）突变体的晶体结构。在A4V结构中，晚餐界面的微小变化导致两种单体的显着重新取向。在I1 13T晶体结构的情况下也可以看到这种效果，但是程度较小。 X射线溶液散射数据表明，在溶液状态下，与野生型超氧化物歧化酶（SOD）相比，与A4V晶体结构相比，这两个突变体都经历了更为明显的构象变化。根据X射线散射数据进行的形状重建说明了这种不稳定的性质。将这些散射数据与在不同温度下测得的牛CuZn SOD的散射数据进行比较，结果表明，在70-80℃的温度范围内，牛酶的散射曲线发生了类似的变化。这些结果表明，与野生型SOD1相比，A4V和I1 13T突变体基本上不稳定，并且家族性肌萎缩性侧索硬化病突变体的这一亚型的致病特性至少部分是由于这种不稳定。

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