Transmembrane β-Barrel Models of α-Synuclein Oligomers
Transmembrane β-Barrel Models of α-Synuclein Oligomers
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DOI：
10.1021/acs.jcim.3c00997
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发表时间：
2023-11-14
影响因子：
5.6
通讯作者：
Lazaridis，Themis
中科院分区：
文献类型：
--
作者：
Maurer，Manuela;Lazaridis，Themis
α-突触核蛋白的聚集与许多神经退行性疾病有关，例如帕金森病和多系统萎缩症，但这些聚集体在疾病发展中的作用尚不清楚。细胞毒性的一种可能机制是某些类型的寡聚物对细胞膜的干扰或透化。然而，此类膜嵌入复合物的高分辨率结构尚未确定。在这里，我们构建并评估了由该蛋白质形成的假定跨膜 β-桶。对 α-突触核蛋白序列的检查揭示了两个可以形成膜嵌入 β-发夹的区域：64-92（NAC）和 35-56，其中包含许多家族性帕金森氏症突变。首先在隐式膜孔中检查这些发夹形成的 β-桶的稳定性，然后通过多微秒全原子模拟进行检查。我们发现 NAC 区域桶保持稳定插入并水合至少 10 μs。 35-56 桶保持稳定插入膜中，但如果所有 His50 均为中性或 His50 被 Q 取代，则脱水和塌陷。如果一半 His50 被双质子化，则桶呈椭圆形，但保持水合状态至少 10 μs。讨论了这些发现对 α-突触核蛋白病理学的可能影响。
The aggregation of α-synuclein is implicated in a number of neurodegenerative diseases, such as Parkinson’s and Multiple System Atrophy, but the role of these aggregates in disease development is not clear. One possible mechanism of cytotoxicity is the disturbance or permeabilization of cell membranes by certain types of oligomers. However, no high-resolution structure of such membrane-embedded complexes has ever been determined. Here we construct and evaluate putative transmembrane β-barrels formed by this protein. Examination of the α-synuclein sequence reveals two regions that could form membrane-embedded β-hairpins: 64–92 (the NAC), and 35–56, which harbors many familial Parkinson’s mutations. The stability of β-barrels formed by these hairpins is examined first in implicit membrane pores and then by multimicrosecond all-atom simulations. We find that a NAC region barrel remains stably inserted and hydrated for at least 10 μs. A 35–56 barrel remains stably inserted in the membrane but dehydrates and collapses if all His50 are neutral or if His50 is replaced by Q. If half of the His50 are doubly protonated, the barrel takes an oval shape but remains hydrated for at least 10 μs. Possible implications of these findings for α-synuclein pathology are discussed.
DOI：
10.1021/acs.jpcb.1c00878
发表时间：
2021-04-15
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Dhar R;Feehan R;Slusky JSG
通讯作者：
Slusky JSG
影响因子：
3.4
作者：
Mihajlovic, Maja;Lazaridis, Themis
通讯作者：
Lazaridis, Themis
影响因子：
2.9
作者：
Durell SR;Guy HR
通讯作者：
Guy HR