Transmembrane Fragment Structures of Amyloid Precursor Protein Depend on Membrane Surface Curvature
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- 作者：Laura Dominguez ; Stephen C. Meredith ; John E. Straub ; David Thirumalai
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：January 22, 2014
- 年：2014
- 卷：136
- 期：3
- 页码：854-857
- 全文大小：281K
- ISSN：1520-5126
文摘
The amyloid 尾 (A尾) peptide associated with Alzheimer鈥檚 disease results from processing of the amyloid precursor protein (APP) by secretases. Cleavage of APP by 尾-secretase produces a 99 amino acid C-terminal fragment of APP (C99) consisting of a single transmembrane (TM) helix. Simulations 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 鈥淕G kink,鈥?centered at two glycines dividing the TM helix. The flexibility of the GG kink is important in the processing of C99 by 纬-secretase. We performed multiscale simulations of C9915鈥?5 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鈥?5 in a DPC surfactant micelle possesses a 鈥淕G kink,鈥?in the TM domain near the dynamic hinge located at G37/G38. Such a kink is not observed in C9915鈥?5 in a POPC lipid bilayer. Intramolecular interaction between the extracellular and TM domains of C9915鈥?5 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 show that the fluctuations of the structural ensemble of APP are strongly influenced by membrane surface curvature.