A novel microdomain-dependent regulatory mechanism of amyloid precursor protein processing

淀粉样前体蛋白加工的新型微结构域依赖性调节机制

• 批准号: 20300125
• 负责人: SAKURAI Takashi
• 金额: $ 12.06万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20300125/
• 关键词: 神経変性疾患; 痴呆; 脂質; 脳神経疾患

Beta-cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) in a membrane microdomain is thought to be a critical regulatory event in generating β-amyloid which is central to the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse brains. APP was associated with cholesterol-dependent microdomains through a network of protein interactions involving X11, Munc18 and syntaxin 1, which largely excluded BACE1. APP-X11-Munc18 interaction mediated inhibitory effects on APP-BACE1 interaction and β-cleavage. We propose a novel regulatory mechanism of APP processing involving microdomain segregation that depends on protein-protein interactions and is controlled by cdk5 phosphorylation.

β分泌酶(BACE1)在膜微区对淀粉样前体蛋白(APP)的β-裂解被认为是产生β-淀粉样蛋白的关键调控事件，而BACE1是阿尔茨海默病发病机制的核心。为了研究这一过程的潜在分子机制，我们分析了小鼠大脑中免疫隔离的、含有APP的、耐洗涤剂的膜。APP通过涉及X11、Munc18和Synaxin 1的蛋白质相互作用网络与胆固醇依赖微域相关，其中很大程度上排除了BACE1。APP-X11-Munc18相互作用介导对APP-BACE1相互作用和β-裂解的抑制作用。我们提出了一种新的APP加工调控机制，涉及微域分离，依赖于蛋白质-蛋白质相互作用，并受CDK5磷酸化控制。

项目成果

Membrane microdomain switching - a new regulatory mechanism of amyloid precursor protein processing

膜微域转换——淀粉样前体蛋白加工的新调控机制

• 发表时间: 2007
• 作者: Sakurai;T;et. al.
• 通讯作者: et. al.

切断端を特異的に認識する抗体を用いたニューレグリン切断機構の解析

使用特异性识别切割末端的抗体分析神经调节蛋白切割机制

• 发表时间: 2010
• 作者: 樫山拓;櫻井隆;樫山拓
• 通讯作者: 樫山拓

Detection of BACE1-mediated activation of neuregulin 1-erbB signaling using a cleavage site specific antibody

使用裂解位点特异性抗体检测 BACE1 介导的神经调节蛋白 1-erbB 信号传导激活

• 发表时间: 2011
• 作者: 樫山拓;櫻井隆
• 通讯作者: 櫻井隆

Detection of BACE1 dependent neuregulin 1 signal using cleaved end specific antibody

使用裂解末端特异性抗体检测 BACE1 依赖性神经调节蛋白 1 信号

• 作者: Sakurai;Takashi;岩里琢治;樫山拓
• 通讯作者: 樫山拓

Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3.

• DOI: 10.1093/hmg/ddn422
• 发表时间: 2009-03-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Tateno, Minako;Kato, Shinsuke;Sakurai, Takashi;Nukina, Nobuyuki;Takahashi, Ryosuke;Araki, Toshiyuki
• 通讯作者: Araki, Toshiyuki