Transmembrane fragment structures of amyloid precursor protein depend on membrane surface curvature.
Transmembrane fragment structures of amyloid precursor protein depend on membrane surface curvature.
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淀粉样前体蛋白的跨膜片段结构取决于膜表面曲率。
DOI：
10.1021/ja410958j
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发表时间：
2014-01-22
影响因子：
15
通讯作者：
Thirumalai D
中科院分区：
文献类型：
--
作者：
Dominguez L;Meredith SC;Straub JE;Thirumalai D
与阿尔茨海默病相关的淀粉样β（Aβ）肽由分泌酶加工淀粉样前体蛋白（APP）产生。在β-分泌酶切割APP后，产生由单个跨膜（TM）螺旋组成的99个氨基酸的APP C-末端片段（C99）。C99同系物的模拟研究和C99在表面活性剂胶束和脂质囊泡中的结构研究表明，一个关键的肽结构基序是一个突出的“GG扭结”，以两个甘氨酸为中心，并划分TM螺旋。GG扭结的柔性在γ-分泌酶加工C99中是重要的。我们进行了多尺度模拟C9915-55在DPC表面活性剂胶束和POPC脂质双层，以阐明膜表面曲率在调节肽结构的作用。在DPC表面活性剂胶束中的C9915-55在TM结构域中具有位于G37/G38处的动态铰链附近的“GG扭结”，而在POPC脂质双层中的C9915-55中未观察到这种扭结。C9915-55的胞外和TM结构域之间的分子内相互作用在胶束环境中增强，影响螺旋稳定性、TM螺旋延伸、暴露于水和在亲脂性区域中的插入深度。我们的研究结果指出，在胶束和双层环境中的C9915-55结构的关键差异，并表明APP的结构系综的波动强烈影响膜表面曲率。
The amyloid β (Aβ) peptide associated with Alzheimer’s Disease results from processing of the amyloid precursor protein (APP) by secretases. Following cleavage of APP by β-secretase, a 99 amino acid C-terminal fragment of APP (C99) is produced consisting of a single transmembrane (TM) helix. Simulation studies of C99 congeners and structural studies of C99 in surfactant micelles and lipid vesicles have shown that a key peptide structural motif is a prominent “GG kink,” centered at two glycines and dividing the TM helix. The flexibility of the GG kink is important in the processing of C99 by γ-secretase. We performed multiscale simulations of C9915–55 in a DPC surfactant micelle and POPC lipid bilayer in order to elucidate the role of membrane surface curvature in modulating the peptide structure. C9915–55 in a DPC surfactant micelle possesses a “GG kink” in the TM domain near the dynamic hinge located at G37/G38, while such a kink is not observed in C9915–55 in a POPC lipid bilayer. Intramolecular interaction between the extracellular and TM domains of C9915–55 is enhanced in the micelle environment, influencing helical stability, TM helix extension, exposure to water, and depth of insertion in the lipophilic region. Our results point to critical differences in C9915–55 structures in micelle and bilayer environments, and show that the fluctuations of the structural ensemble of APP are strongly influenced by membrane surface curvature.
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
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SCHENK, D
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作者：
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通讯作者：
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影响因子：
15
作者：
Miyashita, Naoyuki;Straub, John E.;Thirumalai, D.
通讯作者：
Thirumalai, D.