Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants
Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants
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DOI：
10.1073/pnas.0305143101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Hasnain, SS
中科院分区：
文献类型：
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作者：
Hough, MA;Grossmann, JG;Hasnain, SS
人类铜锌超氧化物歧化酶的90多个点突变导致家族性肌萎缩侧索硬化症，也称为运动神经元疾病。越来越多的证据表明，位于二聚体界面附近的突变子集可能导致突变酶的主要不稳定。我们已经确定了Ala4Val（A4V）和Ile113Thr（I113T）突变体的晶体结构，分别为1.9和1.6埃。在A4V结构中，晚餐界面处的小变化导致两个单体的实质性重新取向。在I1 13T晶体结构的情况下也看到这种效应，但程度较小。X射线溶液散射数据表明，在溶液状态下，这两个突变体进行更明显的构象变化相比，野生型超氧化物歧化酶（SOD）比A4V晶体结构中观察到的。从X射线散射数据的形状重建说明了这种不稳定的性质。比较这些散射数据与那些在不同温度下测得的牛CuZn SOD表明，一个类似的变化，在散射轮廓发生牛酶在70 - 80 degreesC的温度范围。这些结果表明，与野生型SOD 1相比，A4 V和I1 13 T突变体基本上是不稳定的，并且家族性肌萎缩性侧索硬化症突变体的这一子集的致病特性可能至少部分是由于这种不稳定。
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.