Recruitment of the amyloid precursor protein by γ-secretase at the synaptic plasma membrane
Recruitment of the amyloid precursor protein by γ-secretase at the synaptic plasma membrane
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DOI：
10.1016/j.bbrc.2017.10.164
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发表时间：
2018-03-29
影响因子：
3.1
通讯作者：
Dal Peraro, Matteo
中科院分区：
文献类型：
--
作者：
Audagnotto, Martina;Lorkowski, Alexander Kengo;Dal Peraro, Matteo
γ-分泌酶是一种膜包埋的蛋白酶，其切割各种完整膜蛋白的单个跨膜螺旋结构域。淀粉样前体蛋白（APP）是一种重要的底物，因为它与阿尔茨海默病的病理相关性。γ-分泌酶切割APP导致阿尔茨海默病积累，导致β-淀粉样蛋白（An）的机制仍不清楚。粗粒度的分子动力学模拟结果显示，在γ-分泌酶的催化位点附近形成了初始脂筏，并且一旦与APP相互作用，γ-分泌酶的动力学行为发生了变化。这些结果表明APP结合模式的前体，并暗示APP结合后γ-分泌酶在nicastrin（NCT）结构域中的构象发生了变化。(C)2017爱思唯尔公司All rights reserved.
gamma-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 gamma-secretase that leads to accumulation of Alzheimer's disease causing amyloid-beta (An) is still unknown. Coarse-grained molecular dynamics simulations in this study reveal initial lipids raft formation near the catalytic site of gamma-secretase as well as changes in dynamic behavior of gamma-secretase once interacting with APP. The results suggest a precursor of the APP binding mode and hint at conformational changes of gamma-secretase in the nicastrin (NCT) domain upon APP binding. (C) 2017 Elsevier Inc. All rights reserved.