Structural Heterogeneity in Transmembrane Amyloid Precursor Protein Homodimer Is a Consequence of Environmental Selection

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• 作者：Laura Dominguez ; Leigh Foster ; Stephen C. Meredith ; John E. Straub ; D. Thirumalai
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：July 9, 2014
• 年：2014
• 卷：136
• 期：27
• 页码：9619-9626
• 全文大小：480K
• ISSN：1520-5126

文摘

The 99 amino acid C-terminal fragment of amyloid precursor protein (C99), consisting of a single transmembrane (TM) helix, is known to form homodimers. Homodimers can be processed by 纬-secretase to produce amyloid-尾 (A尾) protein, which is implicated in Alzheimer鈥檚 disease (AD). While knowledge of the structure of C99 homodimers is of great importance, experimental NMR studies and simulations have produced varying structural models, including right-handed and left-handed coiled-coils. In order to investigate the structure of this critical protein complex, simulations of the C99_15鈥?5 homodimer in POPC membrane bilayer and DPC surfactant micelle environments were performed using a multiscale approach that blends atomistic and coarse-grained models. The C99_15鈥?5 homodimer adopts a dominant right-handed coiled-coil topology consisting of three characteristic structural states in a bilayer, only one of which is dominant in the micelle. Our structural study, which provides a self-consistent framework for understanding a number of experiments, shows that the energy landscape of the C99 homodimer supports a variety of slowly interconverting structural states. The relative importance of any given state can be modulated through environmental selection realized by altering the membrane or micelle characteristics.