Inhibiting Amyloid Precursor Protein C-terminal Cleavage Promotes an Interaction with Presenilin 1*
Inhibiting Amyloid Precursor Protein C-terminal Cleavage Promotes an Interaction with Presenilin 1*
复制标题
抑制淀粉样前体蛋白 C 末端裂解促进与早老素 1* 的相互作用
DOI：
10.1074/jbc.c000208200
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
P. Fraser
中科院分区：
文献类型：
--
作者：
G. Verdile;R. Martins;Monika Duthie;E. Holmes;P. S. St George;P. Fraser
早老素1 （PS1）在淀粉样蛋白-β的产生中起着关键作用，而淀粉样蛋白是阿尔茨海默病发病机制的核心。研究表明，PS1调控γ-分泌酶对淀粉样蛋白前体蛋白（APP） c端片段（APP- c100）的蛋白水解，这是淀粉样蛋白β生成的最后一步。这种PS1活性的机制和详细途径尚未完全确定，但可能是由于早老素控制的APP片段的运输或可能是固有的PS1蛋白水解活性。我们已经研究了PS1和APP-C100在高分子量早老素复合体中直接相互作用的可能性。然而，APP- c100是快速降解的，如果它形成，那么任何PS1·APP复合物都可能是非常短暂的。为了解决这个问题，我们使用了蛋白酶抑制剂n -乙酰基-亮氨酸-去亮氨酸（LLnL）和溶酶体抑制剂NH4Cl，它们抑制了APP-C100的周转率。在这些条件下，片段的水平明显增加，甘油梯度分析表明，APP-C100转移到与PS1重叠的更高分子质量复合物。免疫沉淀研究表明，大量APP-C100与PS1共沉淀。这些发现表明PS1可能通过直接相互作用介导APP片段的穿梭和/或促进其呈递给γ-分泌酶裂解。
Presenilin 1 (PS1) plays a pivotal role in the production of the amyloid-β protein, which is central to the pathogenesis of Alzheimer's disease. It has been demonstrated that PS1 regulates the γ-secretase proteolysis of the amyloid precursor protein (APP) C-terminal fragment (APP-C100), which is the final step in amyloid-β protein production. The mechanism and detailed pathway of this PS1 activity has yet to be fully resolved, but it may be due to a presenilin-controlled trafficking of the APP fragment or possibly an inherent PS1 proteolytic activity. We have investigated the possibility of a direct interaction of PS1 and the APP-C100 within the high molecular mass presenilin complex. However, the APP-C100 is rapidly degraded, and if it forms, then any PS1·APP complex is likely to be very transitory. To circumvent this problem, we have utilized the protease inhibitor N-acetyl-leucyl-norleucinal (LLnL) and the lysosomotropic agent NH4Cl, which inhibits the turnover of the APP-C100. Under these conditions, levels of the fragment increased appreciably, and as shown by glycerol gradient analysis, the APP-C100 shifted to a higher molecular mass complex that overlapped with PS1. Immunoprecipitation studies demonstrated that a significant population of the APP-C100 co-precipitated with PS1. These findings suggest that PS1 may mediate the shuttling of APP fragments and/or facilitate their presentation for γ-secretase cleavage through a direct interaction.
哺乳动物细胞中淀粉样前体蛋白和早老素之间的相互作用：对阿尔茨海默病发病机制的影响。
DOI：
10.1073/pnas.94.15.8208
发表时间：
1997
影响因子：
11.1
作者：
Xia,W;Zhang,J;Perez,R;Koo,EH;Selkoe,DJ
通讯作者：
Selkoe,DJ
影响因子：
3.3
作者：
Czekay, RP;Orlando, RA;Farquhar, MG
通讯作者：
Farquhar, MG