Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein
Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein
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DOI：
10.1016/j.febslet.2004.09.038
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发表时间：
2004-10-22
期刊：
影响因子：
3.5
通讯作者：
Goedert, M
中科院分区：
文献类型：
--
作者：
Choi, W;Zibaee, S;Goedert, M
α -突触核蛋白的错义突变（A30P和A53T）和野生型蛋白的过量产生导致家族性帕金森病和路易体痴呆。-突触核蛋白是丝状路易小体和路易神经突的主要成分，在神经病理水平上定义了这些疾病。最近，α -突触核蛋白的第三种错义突变（E46K）被描述为遗传性路易体痴呆。在这里，我们研究了这种新突变对α -突触核蛋白磷脂结合和丝组装的功能影响。与野生型蛋白相比，E46K突变导致α -突触核蛋白结合带负电荷脂质体的能力显著增加，这与先前描述的突变不同。E46K突变与A53T突变相同程度地增加了花丝组装率。由E46K α -突触核蛋白形成的细丝通常具有扭曲的形态，交叉间距为43 nm。观察到的对脂质结合和纤维组装的影响可能解释了α -突触核蛋白E46K突变的致病性。(C) 2004年欧洲生化学会联合会。Elsevier B.V.版权所有。
Missense mutations (A30P and A53T) in alpha-synuclein and the overproduction of the wild-type protein cause familial forms of Parkinson's disease and dementia with Lewy bodies. alpha-synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define these diseases at a neuropathological level. Recently, a third missense mutation (E46K) in alpha-synuclein was described in an inherited form of dementia with Lewy bodies. Here, we have investigated the functional effects of this novel mutation on phospholipid binding and filament assembly of alpha-synuclein. When compared to the wild-type protein, the E46K mutation caused a significantly increased ability of alpha-synuclein to bind to negatively charged liposomes, unlike the previously described mutations. The E46K mutation increased the rate of filament assembly to the same extent as the A53T mutation. Filaments formed from E46K alpha-synuclein often had a twisted morphology with a cross-over spacing of 43 nm. The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in alpha-synuclein. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.