Contribution of Alanine-76 and Serine Phosphorylation in α-Synuclein Membrane Association and Aggregation in Yeasts
Contribution of Alanine-76 and Serine Phosphorylation in α-Synuclein Membrane Association and Aggregation in Yeasts
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DOI：
10.4061/2011/392180
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
DebBurman, Shubhik
中科院分区：
文献类型：
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作者：
Fiske, Michael;Valtierra, Stephanie;DebBurman, Shubhik
在帕金森病(PD)中，错误折叠和聚集的α-突触核蛋白在退化的中脑多巴胺能神经元中积聚。α-突触核蛋白中的氨基酸丙氨酸-76以及丝氨酸-87和丝氨酸-129的磷酸化被认为调节其聚集和毒性。然而，它们对α-突触核蛋白膜结合的确切贡献还不是很清楚。我们发现，α-突触核蛋白确实在分裂酵母和萌芽酵母中被磷酸化，这两个模型分别用于评估α-突触核蛋白聚集和膜结合特性。令人惊讶的是，阻断丝氨酸磷酸化(S87A、S129A和S87A/S129A)或模拟丝氨酸磷酸化(S87D、S129D)会改变分裂酵母中的α-突触核蛋白聚集。阻断或模拟这种磷酸化都会增加分裂酵母的膜内结合，但只模拟这种磷酸化会降低芽殖酵母的质膜结合。丙氨酸-76(A76E和A76R)的极性替换突变降低了芽殖酵母中α-突触核蛋白的膜结合，并降低了分裂酵母中的聚集。这些酵母研究扩大了我们对丝氨酸磷酸化和丙氨酸-76对α-突触核蛋白聚集的作用的理解，并首次详细说明了它们对α-突触核蛋白质膜和内膜结合的影响。
In Parkinson's disease (PD), misfolded and aggregated alpha-synuclein protein accumulates in degenerating midbrain dopaminergic neurons. The amino acid alanine-76 in alpha-synuclein and phosphorylation at serine-87 and serine-129 are thought to regulate its aggregation and toxicity. However, their exact contributions to alpha-synuclein membrane association are less clear. We found that alpha-synuclein is indeed phosphorylated in fission yeast and budding yeast, the two models that we employed for assessing alpha-synuclein aggregation and membrane association properties, respectively. Surprisingly, blocking serine phosphorylation (S87A, S129A, and S87A/S129A) or mimicking it (S87D, S129D) altered alpha-synuclein aggregation in fission yeast. Either blocking or mimicking this phosphorylation increased endomembrane association in fission yeast, but only mimicking it decreased plasma membrane association in budding yeast. Polar substitution mutations of alanine-76 (A76E and A76R) decreased alpha-synuclein membrane association in budding yeast and decreased aggregation in fission yeast. These yeast studies extend our understanding of serine phosphorylation and alanine-76 contributions to alpha-synuclein aggregation and are the first to detail their impact on alpha-synuclein's plasma membrane and endomembrane association.