淀粉样β蛋白单体折叠核的结构动力学。
Structural dynamics of the amyloid β-protein monomer folding nucleus.
机构信息
Department of Neurology, University of California, Los Angeles, CA 90095, USA.
出版信息
Biochemistry. 2012 May 15;51(19):3957-9. doi: 10.1021/bi300350p. Epub 2012 May 7.
Abstract
Alzheimer's disease (AD) is linked to the aberrant assembly of the amyloid β-protein (Aβ). The (21)AEDVGSNKGA(30) segment, Aβ(21-30), forms a turn that acts as a monomer folding nucleus. Amino acid substitutions within this nucleus cause familial forms of AD. To determine the biophysical characteristics of the folding nucleus, we studied the biologically relevant acetyl-Aβ(21-30)-amide peptide using experimental techniques (limited proteolysis, thermal denaturation, urea denaturation followed by pulse proteolysis, and electron microscopy) and computational methods (molecular dynamics). Our results reveal a highly stable foldon and suggest new strategies for therapeutic drug development.
摘要
阿尔茨海默病（AD）与淀粉样β-蛋白（Aβ）的异常组装有关。（21）AEDVGSNKGA（30）片段，即 Aβ（21-30），形成一个作为单体折叠核心的环。该核心内的氨基酸取代会导致家族性 AD 形式。为了确定折叠核心的生物物理特性，我们使用实验技术（有限蛋白水解、热变性、尿素变性后脉冲蛋白水解和电子显微镜）和计算方法（分子动力学）研究了具有生物学相关性的乙酰-Aβ（21-30）-酰胺肽。我们的结果揭示了一个高度稳定的折叠核心，并为治疗性药物开发提供了新的策略。
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2
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J Mol Biol. 2008 Jun 13;379(4):815-29. doi: 10.1016/j.jmb.2008.04.028. Epub 2008 May 14.
3
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Curr Protoc Protein Sci. 2006 Dec;Chapter 20:20.11.1-20.11.14. doi: 10.1002/0471140864.ps2011s46.
4
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