Familial mutants of α-synuclein with increased neurotoxicity have a destabilized conformation
Familial mutants of α-synuclein with increased neurotoxicity have a destabilized conformation
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DOI：
10.1074/jbc.c500288200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
Zweckstetter, M
中科院分区：
文献类型：
--
作者：
Bertoncini, CW;Fernandez, CO;Zweckstetter, M
突触前蛋白α-突触核蛋白的A30 P和A53 T突变与家族性帕金森病相关。核磁共振波谱表明帕金森氏症相关突变极大地干扰了α-突触核蛋白天然状态所必需的特定三级相互作用。然而，α-突触核蛋白不是完全展开的，而是在二级结构形成的时间尺度上表现出结构波动，并且当蛋白质稳定性降低时逐渐失去其天然构象。α-突触核蛋白构象异构体集合的再分布可能通过促进自缔合和改变与配体和受体的结合亲和力而成为毒性功能获得的基础。
A30P and A53T mutations of the presynaptic protein alpha- synuclein are associated with familial forms of Parkinson disease. NMR spectroscopy demonstrates that Parkinsonism- linked mutations greatly perturb specific tertiary interactions essential for the native state of alpha- synuclein. However, alpha- synuclein is not completely unfolded but exhibits structural fluctuations on the time scale of secondary structure formation and loses its native conformation gradually when protein stability decreases. The redistribution of the ensemble of alpha- synuclein conformers may underlie toxic gain- of- function by fostering self- association and altered binding affinity to ligands and receptors.