Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions.
Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions.
复制标题
蛋氨酸氧化通过增强自动抑制性分子内长距离相互作用来稳定α-突触核蛋白的无毒寡聚。
DOI：
10.1016/j.bbadis.2009.12.004
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发表时间：
2010-03
影响因子：
6.2
通讯作者：
Uversky, Vladimir N.
中科院分区：
文献类型：
--
作者：
Zhou, Wenbo;Long, Chunmei;Reaney, Stephen H.;Di Monte, Donato A.;Fink, Anthony L.;Uversky, Vladimir N.
氧化应激和突触前蛋白α-突触核蛋白（α-Syn）的聚集参与了帕金森病和其他一些神经退行性疾病的发病机制。各种翻译后修饰，如氧化、硝化、截短等，对α-Syn纤颤的动力学有重要影响。α-Syn是一种典型的天然未折叠蛋白，具有一定的结构残留。最近确定了在C-末端尾（残基120-140）和α-Syn的中心部分（残基30-100）之间存在长程分子内相互作用（Bertoncini等人（2005）Proc Natl Acad Sci U S A 102，1430-1435）。由于α-Syn有四个蛋氨酸，其中两个（Met 1和5）位于N端，另外两个（Met 116和127）位于蛋白质C端的疏水簇中，因此这些残基通过氧化而受到的扰动为研究长程相互作用对α-Syn纤维形成的影响提供了一个良好的模型。在本文中，我们发现Met 1，116和127比Met 5更容易被氧化，这可能是由于天然未折叠的α-Syn中的残留结构。α-Syn蛋白除了C端疏水簇与中心疏水区之间的疏水相互作用外，还存在一些长程静电相互作用。这两种相互作用可能都是α-Syn纤维化的自动抑制剂。甲硫氨酸氧化影响α-Syn中的静电和疏水长程相互作用。最后，H2 O2氧化甲硫氨酸在体外极大地抑制α-Syn纤维化，导致形成相对稳定的寡聚体，其对多巴胺能和GABA能神经元没有毒性。
Oxidative stress and aggregation of the presynaptic protein α-synuclein (α-Syn) are implied in the pathogenesis of Parkinson disease and several other neurodegenerative diseases. Various posttranslational modifications, such as oxidation, nitration and truncation, have significant effects on the kinetics of α-Syn fibrillation in vitro. α-Syn is a typical natively unfolded protein, which possesses some residual structure. The existence of long-range intra-molecular interactions between the C-terminal tail (residues 120–140) and the central part of α-Syn (residues 30–100) was recently established (Bertoncini et al. (2005) Proc Natl Acad Sci U S A 102, 1430–1435). Since α-Syn has four methionines, two of which (Met 1 and 5) are at the N-terminus and the other two (Met 116, 127) are in the hydrophobic cluster at the C-terminus of protein, the perturbation of these residues via their oxidation represents a good model for studying the effect of long-range interaction on α-Syn fibril formation. In this paper we show that Met 1, 116, and 127 are more protected from the oxidation than Met 5 likely due to the residual structure in the natively unfolded α-Syn. In addition to the hydrophobic interactions between the C-terminal hydrophobic cluster and hydrophobic central region of α-Syn, there are some long-range electrostatic interactions in this protein. Both of these interactions likely serve as auto-inhibitors of α-Syn fibrillation. Methionine oxidation affects both electrostatic and hydrophobic long-range interactions in α-Syn. Finally, oxidation of methionines by H2O2 greatly inhibited α-Syn fibrillation in vitro, leading to the formation of relatively stable oligomers, which are not toxic to dopaminergic and GABAergic neurons.
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DOI：
10.1073/pnas.0407146102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Bertoncini, CW;Jung, YS;Zweckstetter, M
通讯作者：
Zweckstetter, M
影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
4.8
作者：
Nielsen, MS;Vorum, H;Jensen, PH
通讯作者：
Jensen, PH
影响因子：
2.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT