The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain
The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain
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DOI：
10.1016/j.bbamem.2011.06.017
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发表时间：
2011-10-01
影响因子：
3.4
通讯作者：
Yahi, Nouara
中科院分区：
文献类型：
--
作者：
Fantini, Jacques;Carlus, Denis;Yahi, Nouara
帕金森病相关α -突触核蛋白是一种淀粉样蛋白，不仅在神经元细胞质中表达，而且在细胞外空间分泌，并通过脂质筏依赖过程内化到胶质细胞。我们之前的研究表明，α -突触核蛋白通过各种病毒和淀粉样蛋白共同的结构基序与筏鞘糖脂相互作用。在这里，我们报告α -突触核蛋白也与胆固醇相互作用，作为评估的表面压力测量含胆固醇单层。利用一组重组片段和合成肽，我们在α -突触核蛋白中确定了两个不同的胆固醇结合结构域。其中一个结构域对应于α -突触核蛋白的倾斜肽（67-78），高亲和力地结合胆固醇，对培养的星形胶质细胞具有毒性。分子模型表明，胆固醇以46度的倾斜角与这种肽结合。α -突触核蛋白还包含一个胆固醇识别共识基序，它对胆固醇的亲和力较低，没有毒性。该基序被包裹在α -突触核蛋白的鞘糖脂结合结构域（34-45）中。在含有胆固醇和鞘糖脂的筏状模型膜中，鞘糖脂的头基团阻止了胆固醇对外源性配体的可及性。然而，胆固醇似乎通过调节鞘糖脂构象来“发出”其存在的信号，从而促进α -突触核蛋白与筏状膜的结合。我们提出α -突触核蛋白与脂筏的关联包括α -突触核蛋白与鞘糖脂的结合（34-45）和促聚变倾斜肽与胆固醇的相互作用（67-78）。巧合的是，病毒（HIV-1、htlv -1、埃博拉病毒）也使用了类似的机制，它们显示一个倾斜的肽，并通过鞘脂/胆固醇依赖的过程与宿主细胞膜融合。(C) 2011 Elsevier B.V.版权所有
Parkinson's disease-associated alpha-synuclein is an amyloidogenic protein not only expressed in the cytoplasm of neurons, but also secreted in the extracellular space and internalized into glial cells through a lipid raft-dependent process. We previously showed that alpha-synuclein interacts with raft glycosphingolipids through a structural motif common to various viral and amyloidogenic proteins. Here we report that alpha-synuclein also interacts with cholesterol, as assessed by surface pressure measurements of cholesterol-containing monolayers. Using a panel of recombinant fragments and synthetic peptides, we identified two distinct cholesterol-binding domains in alpha-synuclein. One of these domains, which corresponds to the tilted peptide of alpha-synuclein (67-78), bound cholesterol with high affinity and was toxic for cultured astrocytes. Molecular modeling suggested that cholesterol binds to this peptide with a tilt angle of 46 degrees. alpha-synuclein also contains a cholesterol recognition consensus motif, which had a lower affinity for cholesterol and was devoid of toxicity. This motif is encased in the glycosphingolipid-binding domain (34-45) of alpha-synuclein. In raft-like model membranes containing both cholesterol and glycosphingolipids, the head groups of glycosphingolipids prevented the accessibility of cholesterol to exogenous ligands. Nevertheless, cholesterol appeared to 'signal' its presence by tuning glycosphingolipid conformation, thereby facilitating alpha-synuclein binding to raft-like membranes. We propose that the association of alpha-synuclein with lipid rafts involves both the binding of alpha-synuclein (34-45) to glycosphingolipids, and the interaction of the fusogenic tilted peptide (67-78) with cholesterol. Coincidentally, a similar mechanism is used by viruses (HIV-1, HTLV-I, Ebola) which display a tilted peptide and fuse with host cell membranes through a sphingolipid/cholesterol-dependent process. (C) 2011 Elsevier B.V. All rights reserved.