Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.
Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.
复制标题
由家族性肌萎缩侧索硬化症相关突变 A4V 引起的单体 CuZn 超氧化物歧化酶的结构变化。
DOI：
10.1016/j.bpj.2009.06.043
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发表时间：
2009
影响因子：
3.4
通讯作者：
Daggett,Valerie
中科院分区：
文献类型：
--
作者：
Schmidlin,Tom;Kennedy,BrianK;Daggett,Valerie
肌萎缩性侧索硬化症（ALS）是一种进行性运动神经元退行性疾病，其遗传形式为家族性ALS (fALS)，与分布在Cu-Zn超氧化物歧化酶蛋白（SOD1）中的100多种不同的点突变有关。该疾病可能是由于突变SOD1的错误折叠、寡聚化和最终聚集引起的功能毒性增加，但尚不清楚结构多样的突变如何导致共同的疾病表型。利用分子动力学模拟，研究了载子单体fals相关突变蛋白A4V的行为，以阐明蛋白质的特征结构变化，这些变化可能允许突变形式不正确地与其他单体亚基结合。模拟结果表明，突变蛋白总体上不如WT蛋白稳定，残基-残基接触的变化导致二聚体和金属结合位点的不稳定，非天然接触的稳定导致错误折叠状态。这些发现为不同的实验观察提供了统一的解释，允许更好地理解伴随SOD1结构完整性丧失的残基接触的改变，并提示代偿性变化可能稳定突变结构的位点。
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease, and the inherited form, familial ALS (fALS), has been linked to over 100 different point mutations scattered throughout the Cu-Zn superoxide dismutase protein (SOD1). The disease is likely due to a toxic gain of function caused by the misfolding, oligomerization, and eventual aggregation of mutant SOD1, but it is not yet understood how the structurally diverse mutations result in a common disease phenotype. The behavior of the apo-monomer fALS-associated mutant protein A4V was explored using molecular-dynamics simulations to elucidate characteristic structural changes to the protein that may allow the mutant form to improperly associate with other monomer subunits. Simulations showed that the mutant protein is less stable than the WT protein overall, with shifts in residue-residue contacts that lead to destabilization of the dimer and metal-binding sites, and stabilization of nonnative contacts that leads to a misfolded state. These findings provide a unifying explanation for disparate experimental observations, allow a better understanding of alterations of residue contacts that accompany loss of SOD1 structural integrity, and suggest sites where compensatory changes may stabilize the mutant structure.