Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
Phys Chem Chem Phys. 2018 Nov 7;20(43):27294-27304. doi: 10.1039/c8cp04138e.
γ-Secretase (GS) is a multi-subunit membrane-embedded aspartyl protease that cleaves more than 80 integral membrane proteins, including the amyloid precursor protein (APP) to produce the amyloid-β (Aβ) peptide. Oligomerization and aggregation of the 42-amino acid length Aβ isoform in the brain has been associated with the development and progression of Alzheimer's disease (AD). Based on recent experimental structural studies and using multiscale computational modeling approaches, the conformational states and protein-membrane interactions of the GS complex embedded in six homogeneous and six heterogeneous lipid bilayers were characterized. In order to identify potential lipid and cholesterol binding sites, GS regions with high lipid/cholesterol occupancy values were analyzed using atomistic and coarse-grained simulations. Long lipid residence times were observed to be correlated with a large number of hydrogen bonds between the charged headgroups and key GS amino acids. This observation provides a plausible explanation for the inhibition of GS by charged lipids observed in previous experimental studies. Computed lateral pressure profiles suggest that higher transmembrane pressures favor active state conformations of the catalytic subunit. A probable mechanism for the regulation of the local stress response in cholesterol-rich multicomponent lipid bilayers is identified. Finally, it is demonstrated that interactions between the nicastrin extracellular domain and lipid headgroups leads to a compact structural conformation of the GS complex. Overall, this study provides valuable insight into the effect of bilayer lipid composition on the GS structural ensemble and its function.
γ-分泌酶（GS）是一种多亚基膜嵌入天冬氨酸蛋白酶，可切割超过 80 种完整膜蛋白，包括淀粉样前体蛋白（APP）以产生淀粉样β（Aβ）肽。大脑中 42 个氨基酸长度的 Aβ同种型的寡聚化和聚集与阿尔茨海默病（AD）的发展和进展有关。基于最近的实验结构研究，并使用多尺度计算建模方法，对嵌入在六个均匀和六个非均匀脂质双层中的 GS 复合物的构象状态和蛋白-膜相互作用进行了表征。为了确定潜在的脂质和胆固醇结合位点，使用原子和粗粒模拟分析了具有高脂质/胆固醇占有率的 GS 区域。观察到长脂质停留时间与带电荷的头基团和关键 GS 氨基酸之间的大量氢键相关。这一观察结果为先前实验研究中观察到的带电脂质对 GS 的抑制提供了合理的解释。计算的侧向压力曲线表明，较高的跨膜压力有利于催化亚基的活性构象。确定了富含胆固醇的多组分脂质双层中局部应激反应调节的可能机制。最后，证明尼卡斯特林细胞外结构域与脂质头基团之间的相互作用导致 GS 复合物的结构构象紧凑。总的来说，这项研究深入了解了双层脂质组成对 GS 结构整体及其功能的影响。
