Structural disorder of monomeric α-synuclein persists in mammalian cells
Structural disorder of monomeric α-synuclein persists in mammalian cells
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DOI：
10.1038/nature16531
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发表时间：
2016-02-04
期刊：
影响因子：
64.8
通讯作者：
Selenko, Philipp
中科院分区：
文献类型：
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作者：
Theillet, Francois-Xavier;Binolfi, Andres;Selenko, Philipp
人淀粉样蛋白α-突触核蛋白的细胞内聚集与帕金森病有因果关系。虽然分离的蛋白质本质上是无序的，但其在哺乳动物细胞中的天然结构尚不清楚。在这里，我们使用核磁共振（NMR）和电子顺磁共振（EPR）光谱，以获得原子分辨率的见解在不同的哺乳动物细胞类型的α-突触核蛋白的结构和动力学。我们发现，单体α-突触核蛋白的无序性质是稳定地保存在非神经元和神经元细胞。在生理细胞条件下，α-突触核蛋白被氨基末端乙酰化，并采用比在缓冲液中时更紧凑的构象，其中易于聚集的非淀粉样蛋白-β组分（NAC）区域的残基被屏蔽而不暴露于细胞质，这可能抵消自发聚集。这些结果表明，不同类型的拥挤的细胞内环境并不固有地促进α-突触核蛋白寡聚化，更一般地说，内在的结构紊乱在哺乳动物细胞中是可持续的。
Intracellular aggregation of the human amyloid protein alpha-synuclein is causally linked to Parkinson's disease. While the isolated protein is intrinsically disordered, its native structure in mammalian cells is not known. Here we use nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of alpha-synuclein in different mammalian cell types. We show that the disordered nature of monomeric alpha-synuclein is stably preserved in non-neuronal and neuronal cells. Under physiological cell conditions, alpha-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-beta component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. These results establish that different types of crowded intracellular environments do not inherently promote alpha-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells.