Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.
Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.
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DOI：
10.1016/j.bpj.2010.02.001
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发表时间：
2010-05
影响因子：
3.4
通讯作者：
Chang-chun Lee;Yen Sun;Huey W. Huang
中科院分区：
文献类型：
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作者：
Chang-chun Lee;Yen Sun;Huey W. Huang
Jarrett和Lansbury的成核依赖聚合模型描述了大量不同蛋白质和多肽的β-淀粉样蛋白形成的一般过程。在这里，我们讨论一个膜介导的成核导致β聚集的情况。我们研究了膜介导的多肽穿透的构象变化，我们的研究结果使我们得到了膜介导的Jarrett-Lansbury模型的自由能描述。与原型β-淀粉样多肽阿尔茨海默氏症Aβ1-40一样，穿透蛋白在溶液中是随机卷曲的单体，但在阴离子脂膜存在下会改变为α螺旋或β样构象。我们测量了四种不同链不饱和度的不同脂类的膜结合构象与其对双层厚度的影响之间的相关性。我们发现了一种新的脂链对多肽构象的影响。我们的结果表明，脂质双层的界面为以α-螺旋形式穿透提供了能量有利的结合部位。然而，增加结合分子/脂质的比例会将结合态的能级提高到更高的水平，这有利于产生小的β聚集体。随着聚集体的增大，与β聚集体的结合变得更加有利。在巨大的单层囊泡表面可见多肽聚集体。因此，膜结合促进了核依赖的β聚集，这可能是膜介导的β-淀粉样蛋白形成的一般途径的原型。
Jarrett and Lansbury's nucleation-dependent polymerization model describes the generic process ofβ-amyloid formation for a large number of diverse proteins and peptides. Here, we discuss a case of membrane-mediated nucleation that leads toβ-aggregation. We studied the membrane-mediated conformation changes of the peptide penetratin, and the results of our study led us to a free-energy description for a membrane-mediated version of the Jarrett-Lansbury model. Like the prototypeβ-amyloid peptide Alzheimer's Aβ1–40, penetratin is a random-coil monomer in solution but changes toα-helical orβ-like conformations in the presence of anionic lipid membranes. We measured the correlations between the membrane-bound conformation of penetratin and its effect on the bilayer thickness in four different lipids with various degrees of chain unsaturation. We found a new lipid chain effect on peptide conformation. Our results showed that the interface of a lipid bilayer provided energetically favorable binding sites for penetratin in theα-helical form. However, increasing the bound molecules/lipid ratio elevated the energy level of the bound states toward a higher level that favored creation of smallβ-aggregates. The binding to theβ-aggregate became more energetically favorable as the aggregate grew larger. The peptide aggregates were visible on the surface of giant unilamellar vesicles. Thus, membrane binding facilitates nucleation-dependentβ-aggregation, which could be the prototype for the general membrane-mediated pathway toβ-amyloid formation.