Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland; Swiss Institute of Bioinformatcs (SIB), Lausanne 1015, Switzerland.
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland; Swiss Institute of Bioinformatcs (SIB), Lausanne 1015, Switzerland.
Biochem Biophys Res Commun. 2018 Mar 29;498(2):334-341. doi: 10.1016/j.bbrc.2017.10.164. Epub 2017 Oct 31.
Γ-secretase is a membrane-embedded protease that cleaves single transmembrane helical domains of various integral membrane proteins. The amyloid precursor protein (APP) is an important substrate due to its pathological relevance to Alzheimer's disease. The mechanism of the cleavage of APP by γ-secretase that leads to accumulation of Alzheimer's disease causing amyloid-β (Aβ) is still unknown. Coarse-grained molecular dynamics simulations in this study reveal initial lipids raft formation near the catalytic site of γ-secretase as well as changes in dynamic behavior of γ-secretase once interacting with APP. The results suggest a precursor of the APP binding mode and hint at conformational changes of γ-secretase in the nicastrin (NCT) domain upon APP binding.
γ-分泌酶是一种膜嵌入蛋白酶，可切割各种跨膜螺旋域的单一跨膜螺旋域的各种完整膜蛋白。淀粉样前体蛋白（APP）是一个重要的底物，因为它与阿尔茨海默病的病理相关。γ-分泌酶切割 APP 导致阿尔茨海默病致病淀粉样β（Aβ）积累的机制仍不清楚。本研究中的粗粒度分子动力学模拟揭示了γ-分泌酶催化位点附近最初的脂筏形成，以及与 APP 相互作用后γ-分泌酶动态行为的变化。结果表明了 APP 结合模式的前体，并暗示了 APP 结合后尼卡斯特林（NCT）域中 γ-分泌酶构象的变化。
