Polymorphism of amyloid β peptide in different environments: implications for membrane insertion and pore formation.
Polymorphism of amyloid β peptide in different environments: implications for membrane insertion and pore formation.
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DOI：
10.1039/c1sm05162h
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发表时间：
2011-05-09
期刊：
影响因子：
3.4
通讯作者：
Lal R
中科院分区：
文献类型：
--
作者：
Arce FT;Jang H;Ramachandran S;Landon PB;Nussinov R;Lal R
β 淀粉样蛋白 (Aβ) 肽被认为与阿尔茨海默病和唐氏综合症等神经退行性疾病有关。它们形成大量的多晶型结构，包括膜中的异质离子孔以及表面和溶液中不同类型的纤维状和球状结构。由于结构和致病性之间可能存在关系，了解这些结构的起源以及影响其发生的因素具有重大的生物医学意义。在这里，我们使用原子力显微镜（AFM）和分子动力学（MD）模拟来证明，在室温下，体内产生并在体外显示有毒的截短的Aβ肽在疏水性石墨表面上形成纤维状结构，但不在亲水性云母或脂质双层上形成纤维状结构。我们的结果表明，有毒孔和纤维状多态性组织可以用全长 Aβ 和其他淀粉样蛋白观察到的 U 形 β 链转角 β 链结构基序以及界面的理化性质来解释。疏水性、截短的 Aβ 与其环境的相互作用表明，通用淀粉样蛋白基序可以提供孔和纤维结构之间的联系，并表明具有不同理化性质的表面可以将多态性景观转向其他构象状态。
Amyloid-β (Aβ) peptides are thought to be involved in neurodegenerative diseases such as Alzheimer's disease and Down's syndrome. They form a large number of polymorphic structures, including heterogeneous ionic pores in membranes as well as different types of fibrillar and globular structures on surfaces and in solution. Understanding the origin of these structures and the factors that influence their occurrence is of great biomedical interest because of the possible relationship between structure and pathogenicity. Here, we use atomic force microscopy (AFM) and molecular dynamics (MD) simulations to demonstrate that at room temperature a truncated Aβ peptide which is generated in vivo and shown to be toxic in vitro forms fibrillar structures on hydrophobic graphite surfaces, but not on hydrophilic mica or lipid bilayers. Our results suggest that the toxic pores and fibrillar polymorphic organizations can be explained in terms of the U-shaped β-strand-turn-β-strand structural motif observed for full length Aβ and other amyloids, as well as the physicochemical properties at the interfaces. The interactions of the hydrophobic, truncated Aβ with its environment illustrate that the universal amyloid motif can provide a link between the pore and fibrillar structures and indicate that surfaces with different physicochemical properties can shift the polymorphic landscape toward other conformational states.