一种稳定的脂诱导聚集的α-突触核蛋白。
A stable lipid-induced aggregate of alpha-synuclein.
机构信息
Department of Molecular Physics, Leiden University, P.O. Box 9504, 2300 RA Leiden, The Netherlands.
出版信息
J Am Chem Soc. 2010 Mar 31;132(12):4080-2. doi: 10.1021/ja909247j.
The Parkinson's disease-related protein alpha-Synuclein (alphaS) is a 140 residue intrinsically disordered protein. Its membrane-binding properties are thought to be relevant for its physiological or pathologic activity. Here, the interaction of alphaS with POPG [1-Palmitoyl-2-Oleoyl-sn-Glycero-3-(Phosphorac-(1-glycerol))] small unilamellar vesicles (SUVs) is investigated by spin-label EPR using double electron-electron resonance (DEER). Intermolecular distances between four single mutants reveal that well-defined aggregates are formed. The data suggest a coexistence of two dimer structures with main interactions in the helix 2, encompassing residues 50-100. Previously, the horseshoe conformation was detected by intramolecular restraints obtained by DEER on alphaS double mutants (Drescher et al. J. Am. Chem. Soc. 2008, 130, 7796). The present study suggests that interdigitation of two monomers in the aggregate fills the void between the two helices of each of the monomers thus providing a rationale for the horseshoe structure. This aggregate is lipid induced and affects the structure of the POPG SUVs, which become leaky and diminish in size upon contact with alphaS suggesting a possible origin of conflicting results in the recent literature (Jao et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105 (50), 19666; Georgieva et al. J. Am. Chem. Soc. 2008, 130 (39), 12856; Bortolus et al. J. Am. Chem. Soc. 2008, 130, 6690).
帕金森病相关蛋白α-突触核蛋白（αS）是一种含有 140 个残基的无序蛋白。其与膜的结合特性被认为与其生理或病理活性有关。本文使用双电子电子共振（DEER）自旋标记电子顺磁共振（EPR）研究了 αS 与 POPG [1-棕榈酰-2-油酰基-sn-甘油-3-（磷酰基-（1-甘油））]小单层囊泡（SUV）的相互作用。四个单突变体的分子间距离表明形成了明确的聚集体。数据表明存在两种二聚体结构的共存，其主要相互作用位于包含残基 50-100 的螺旋 2 中。此前，通过对 αS 双突变体（Drescher 等人，J. Am. Chem. Soc.，2008，130，7796）进行 DEER 获得的分子内限制，检测到了马蹄形构象。本研究表明，聚集体中两个单体的交错填补了每个单体的两个螺旋之间的空隙，从而为马蹄形结构提供了一个理由。这种聚集体是由脂质诱导的，影响了 POPG SUV 的结构，与 αS 接触后 SUV 变得渗漏且尺寸减小，这表明了近期文献中相互矛盾结果的可能起源（Jao 等人，Proc. Natl. Acad. Sci. U.S.A.，2008，105（50），19666; Georgieva 等人，J. Am. Chem. Soc.，2008，130（39），12856; Bortolus 等人，J. Am. Chem. Soc.，2008，130，6690）。
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