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首页> 外文期刊>Biochemistry >Structural Role of Compensatory Amino Acid Replacements in the α-Synuclein Protein
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Structural Role of Compensatory Amino Acid Replacements in the α-Synuclein Protein

机译：α-突触核蛋白蛋白中补偿性氨基酸替代的结构作用

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A subset of familial Parkinson’s disease (PD) cases is associated with the presence of disease-causing point mutations in human α-synuclein [huAS(wt)], including A53T. Surprisingly, the human neurotoxic amino acid 53T is present in non-primate, wild-type sequences of α-synucleins, including that expressed by mice [mAS(wt)]. Because huAS(A53T) causes neurodegeneration when expressed in rodents, the amino acid changes between the wild-type human protein [huAS(wt)] and mAS(wt) might act as intramolecular suppressors of A53T toxicity in the mouse protein, restoring its physiological structure and function. The lack of structural information for mAS(wt) in aqueous solution has prompted us to conduct a comparative molecular dynamics study of huAS(wt), huAS(A53T), and mAS(wt) in water at 300 K. The calculations are based on an ensemble of nuclear magnetic resonance-derived huAS(wt) structures. huAS(A53T) turns out to be more flexible and less compact than huAS(wt). Its central (NAC) region, involved in fibril formation by the protein, is more solvent-exposed than that of the wild-type protein, in agreement with nuclear magnetic resonance data. The compactness of mAS(wt) is similar to that of the human protein. In addition, its NAC region is less solvent-exposed and more rigid than that of huAS(A53T). All of these features may be caused by an increase in the level of intramolecular interactions on passing from huAS(A53T) to mAS(wt). We conclude that the presence of “compensatory replacements” in the mouse protein causes a significant change in the protein relative to huAS(A53T), restoring features not too dissimilar to those of the human protein.
机译：家族性帕金森病（PD）病例的一部分与人类α-突触核蛋白[huAS（wt）]（包括A53T）中的致病点突变有关。令人惊讶地，人神经毒性氨基酸53T存在于α-突触核蛋白的非灵长类野生型序列中，包括小鼠[mAS（wt）]表达的序列。因为huAS（A53T）在啮齿动物中表达时会引起神经退行性变，所以野生型人类蛋白[huAS（wt）]和mAS（wt）之间的氨基酸变化可能充当了小鼠蛋白中A53T毒性的分子内抑制剂，从而恢复了其生理性结构和功能。水溶液中mAS（wt）的结构信息的缺乏促使我们进行了在300 K水中的huAS（wt），huAS（A53T）和mAS（wt）的比较分子动力学研究。计算基于核磁共振衍生的huAS（wt）结构的集合。事实证明，huAS（A53T）比huAS（wt）更灵活，更紧凑。与核磁共振数据相符，其中央（NAC）区域参与了蛋白质的原纤维形成，与野生型蛋白质相比，其暴露于溶剂的程度更高。 mAS（wt）的紧密度类似于人蛋白质的紧密度。此外，它的NAC区比huAS（A53T）的溶剂区少，并且刚性更高。所有这些特征可能是由于从huAS（A53T）传递到mAS（wt）时分子内相互作用水平增加所致。我们得出的结论是，相对于huAS（A53T），小鼠蛋白质中“补偿性替代”的存在会引起蛋白质的显着变化，从而恢复与人类蛋白质不太相似的特征。

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