Zibaee Shahin, Makin O Sumner, Goedert Michel, Serpell Louise C
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
Protein Sci. 2007 May;16(5):906-18. doi: 10.1110/ps.062624507.
Fibrillar inclusions are a characteristic feature of the neuropathology found in the alpha-synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Familial forms of alpha-synucleinopathies have also been linked with missense mutations or gene multiplications that result in higher protein expression levels. In order to form these fibrils, the protein, alpha-synuclein (alpha-syn), must undergo a process of self-assembly in which its native state is converted from a disordered conformer into a beta-sheet-dominated form. Here, we have developed a novel polypeptide property calculator to locate and quantify relative propensities for beta-strand structure in the sequence of alpha-syn. The output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of the beta-sheet core in alpha-syn fibrils. In particular, the plot features three peaks, the largest of which is completely absent for the nonfibrillogenic protein, beta-syn. We also report similar significant correlations for the Alzheimer's disease-related proteins, Abeta and tau. A substantial region of alpha-syn is capable [corrected] of converting from its disordered conformation into a long [corrected] alpha-helical protein. We have developed the aforementioned algorithm to locate and quantify the alpha-helical hydrophobic moment in the amino acid sequence of alpha-syn. As before, the output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of alpha-helical structure in membrane bilayer-associated alpha-syn.
纤维状包涵体是在α-突触核蛋白病（如帕金森病、路易体痴呆和多系统萎缩）的神经病理学中发现的特征性表现。α-突触核蛋白病的家族形式也与错义突变或基因倍增有关，这些会导致更高的蛋白质表达水平。为了形成这些纤维，蛋白质α-突触核蛋白（α-syn）必须经历一个自组装过程，在此过程中其天然状态从无序构象转变为以β-折叠为主的形式。在这里，我们开发了一种新型的多肽性质计算器，用于定位和量化α-syn序列中β-链结构的相对倾向。该算法的输出以简单的x-y图形式呈现，发现与α-syn纤维中β-折叠核心的位置非常吻合。特别是，该图有三个峰值，其中最大的峰值在非纤维形成蛋白β-syn中完全不存在。我们还报告了与阿尔茨海默病相关蛋白Aβ和tau的类似显著相关性。α-syn的一个相当大的区域能够从其无序构象转变为长的α-螺旋蛋白。我们开发了上述算法来定位和量化α-syn氨基酸序列中的α-螺旋疏水矩。和之前一样，该算法的输出以简单的x-y图形式呈现，发现与膜双层相关的α-syn中α-螺旋结构的位置非常吻合。
