Structures of beta-amyloid peptide 1-40, 1-42, and 1-55-the 672-726 fragment of APP-in a membrane environment with implications for interactions with gamma-secretase.
Structures of beta-amyloid peptide 1-40, 1-42, and 1-55-the 672-726 fragment of APP-in a membrane environment with implications for interactions with gamma-secretase.
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DOI：
10.1021/ja905457d
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发表时间：
2009-12-16
影响因子：
15
通讯作者：
Thirumalai, D.
中科院分区：
文献类型：
--
作者：
Miyashita, Naoyuki;Straub, John E.;Thirumalai, D.
β-淀粉样蛋白（Aβ）聚集与神经退行性阿尔茨海默病（Alzheimer's Disease，AD）有关，并与包括脑淀粉样血管病在内的其他淀粉样疾病有关。Aβ肽通过跨膜蛋白酶切割淀粉样前体蛋白（APP）产生。确定膜中β-淀粉样肽的结构对于为切割机制提供分子基础至关重要。我们报道了用复制交换分子动力学模拟方法确定的淀粉样β肽（Aβ1-40和Aβ1-42）以及APP的672-726片段（简称Aβ1-55）在膜环境中的结构。发现Aβ1-40有两个螺旋结构域A（13-22）和B（30-35），在23-27处有一个I型β转角。该肽位于膜和溶剂之间的界面处。观察到域A中的大幅波动。观察到Aβ1-40的主要模拟三级结构与模拟Aβ1-42结构相似。然而，有观察到的差异，其特征在于由二维自由能表面的整体构象合奏。APP片段（Aβ1-55）具有较长的跨膜螺旋。阐明了跨膜区的位置和膜结构的集合。提出了跨膜Aβ1-55结构（切割前）和Aβ1-40结构（切割后）之间的构象转变。
Aggregation Amyloid β (Aβ) peptide has been linked to the neurodegenerative Alzheimer’s Disease and implicated in other amyloid diseases including cerebral amyloid angiopathy. Aβ peptide is generated by cleavage of the amyloid precursor protein (APP) by transmembrane proteases. It is crucial to determine the structures of β-amyloid peptides in a membrane to provide a molecular basis for the cleavage mechanism. We report the structures of amyloid β peptide (Aβ1–40 and Aβ1–42) as well as the 672–726 fragment of APP (referred to as Aβ1–55) in a membrane environment determined by replica-exchange molecular dynamics simulation. Aβ1–40 is found to have two helical domains A (13–22) and B(30–35) and a type I β turn at 23–27. The peptide is localized at the interface between membrane and solvent. Substantial fluctuations in domain A are observed. The dominant simulated tertiary structure of Aβ1–40 is observed to be similar to the simulated Aβ1–42 structure. However, there are differences observed in the overall conformational ensemble as characterized by the two-dimensional free energy surfaces. The fragment of APP (Aβ1–55) is observed to have a long transmembrane helix. The position of the transmembrane region and ensemble of membrane structures are elucidated. The conformational transition between the transmembrane Aβ1–55 structure, prior to cleavage, and the Aβ1–40 structure, following cleavage, is proposed.
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影响因子：
2.9
作者：
Funamoto, S;Morshima-Kawashima, M;Ihara, Y
通讯作者：
Ihara, Y
DOI：
10.1073/pnas.0502006102
发表时间：
2005-04-26
影响因子：
11.1
作者：
Borreguero, JM;Urbanc, B;Stanley, HE
通讯作者：
Stanley, HE
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1073/pnas.90.2.567
发表时间：
1993-01-15
影响因子：
11.1
作者：
ARISPE, N;ROJAS, E;POLLARD, HB
通讯作者：
POLLARD, HB
影响因子：
8.6
作者：
GARCIA, AE
通讯作者：
GARCIA, AE