Dominguez Laura, Foster Leigh, Meredith Stephen C, Straub John E, Thirumalai D
Department of Chemistry, Boston University , Boston, Massachusetts 02215, United States.
J Am Chem Soc. 2014 Jul 9;136(27):9619-26. doi: 10.1021/ja503150x. Epub 2014 Jun 30.
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 γ-secretase to produce amyloid-β (Aβ) protein, which is implicated in Alzheimer's 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(15-55) 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(15-55) 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.
淀粉样前体蛋白（C99）的99个氨基酸C末端片段由单个跨膜（TM）螺旋组成，已知其能形成同二聚体。同二聚体可被γ-分泌酶加工产生淀粉样β（Aβ）蛋白，该蛋白与阿尔茨海默病（AD）有关。虽然了解C99同二聚体的结构非常重要，但实验性核磁共振研究和模拟产生了不同的结构模型，包括右手和左手卷曲螺旋。为了研究这种关键蛋白复合物的结构，使用结合原子模型和粗粒度模型的多尺度方法，对POPC膜双层和DPC表面活性剂胶束环境中的C99(15 - 55)同二聚体进行了模拟。C99(15 - 55)同二聚体在双层中采用由三种特征结构状态组成的主要右手卷曲螺旋拓扑结构，其中只有一种在胶束中占主导地位。我们的结构研究为理解许多实验提供了一个自洽的框架，表明C99同二聚体的能量景观支持多种缓慢相互转化的结构状态。任何给定状态的相对重要性可通过改变膜或胶束特性实现的环境选择来调节。
