Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology , Beijing 100029, China.
J Chem Inf Model. 2017 Jun 26;57(6):1375-1387. doi: 10.1021/acs.jcim.7b00196. Epub 2017 Jun 9.
The lipid raft microenvironment is implicated in the generation of the pathological amyloid-β (Aβ) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment. The results showed that C99 was anchored at the boundary of the lipid raft relying on the conserved hydrophobic motif of VxxAxxxVxxxV. Moreover, the dimerization of C99 was greatly destabilized by the lipid raft, which led to a susceptible switching packing conformation. The molecular driving forces were derived from the combined regulation of the saturated lipids and cholesterols rather than from the simple binding competition of cholesterol in the C99 dimerization. The molecular details of the differential dimerization in the raft-forming and bulk fluid bilayer environments were compared, and the structural information was helpful for further understanding the enzymolysis responsiveness of APP.
脂筏微环境与神经退行性疾病相关的淀粉样前体蛋白 (APP) 中病理性淀粉样β (Aβ) 物种的产生有关。有证据表明，APP 形成跨膜同源二聚体，其结构随膜成分的变化而变化。然而，在分隔的膜中，二聚化和结构改变对淀粉样形成过程的分子责任在很大程度上仍不清楚。在这里，我们进行了多次粗粒化 (CG) 模拟，以探索受脂筏微环境影响的跨膜 APP 结构域 (称为 C99) 的行为偏好。结果表明，C99 依靠 VxxAxxxVxxxV 保守的疏水区锚定在脂筏的边界上。此外，脂筏大大破坏了 C99 的二聚化，导致易发生切换的包装构象。分子驱动力来自饱和脂质和胆固醇的联合调节，而不是胆固醇在 C99 二聚化中的简单结合竞争。比较了在形成脂筏和体相流体双层环境中的差异二聚化的分子细节，结构信息有助于进一步理解 APP 的酶切反应性。
