gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins.
gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins.
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DOI：
10.1021/bi027375c
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发表时间：
2003-06
期刊：
影响因子：
2.9
通讯作者：
Dominic M. Walsh;J. Fadeeva;M. LaVoie;K. Paliga;S. Eggert;W. T. Kimberly;W. Wasco;Dennis J. Selkoe-Dennis-J.-S
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文献类型：
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作者：
Dominic M. Walsh;J. Fadeeva;M. LaVoie;K. Paliga;S. Eggert;W. T. Kimberly;W. Wasco;Dennis J. Selkoe-Dennis-J.-S
淀粉样前体蛋白(APP)的受控膜内蛋白分解(RIP)可产生淀粉样β蛋白(Abeta)，这可能是阿尔茨海默病(AD)的病因，因此是治疗干预的重要靶点。然而，越来越多的人达成共识，认为产生Abeta的蛋白水解酶之一的伽马分泌酶对APP和越来越多的其他受体的信号转导也是至关重要的。APP是一个基因家族的成员，该家族包括两个淀粉样前体蛋白APLP1和APLP2。尽管APP和APLP经历了相似的蛋白质降解过程，但关于它们的伽马分泌酶生成的胞内域(ICD)的作用的信息很少。在这里，我们发现APLP1和2经历了类似于APP的早老素依赖的RIP，导致每个蛋白质释放大约6 kDa的ICD。每个ICD都被胰岛素降解酶样活性降解，但它们可以被FE65家族成员稳定并转移到细胞核。鉴于APP加工的调节是一个治疗目标，APLP的处理方式与APP相似，任何旨在改变APP蛋白分解的策略都必须考虑APLP 1和APLP 2对信号传递的可能影响。
Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) produces amyloid beta-protein (Abeta), the probable causative agent of Alzheimer's disease (AD), and is therefore an important target for therapeutic intervention. However, there is a burgeoning consensus that gamma-secretase, one of the proteases that generates Abeta, is also critical for the signal transduction of APP and a growing list of other receptors. APP is a member of a gene family that includes two amyloid precursor-like proteins, APLP1 and APLP2. Although APP and the APLPs undergo similar proteolytic processing, there is little information about the role of their gamma-secretase-generated intracellular domains (ICDs). Here, we show that APLP1 and 2 undergo presenilin-dependent RIP similar to APP, resulting in the release of a approximately 6 kDa ICD for each protein. Each of the ICDs are degraded by an insulin degrading enzyme-like activity, but they can be stabilized by members of the FE65 family and translocate to the nucleus. Given that modulation of APP processing is a therapeutic target and that the APLPs are processed in a manner similar to APP, any strategy aimed at altering APP proteolysis will have to take into account possible effects on signaling by APLP 1 and 2.