Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase.
Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase.
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DOI：
10.3389/fphys.2014.00463
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发表时间：
2014
影响因子：
4
通讯作者：
Morishima-Kawashima M
中科院分区：
文献类型：
--
作者：
Morishima-Kawashima M
淀粉样蛋白(Aβ-Protein，Aβ)在阿尔茨海默病的发病机制中起核心作用，阿尔茨海默病是最常见的年龄相关性神经退行性疾病。β是由β-分泌酶对β-淀粉样前体蛋白(APP)的β-羧基末端片段(γCTF)进行膜内蛋白分解而产生的。γ-分泌酶最初的切割发生在βCTF的膜/胞质边界，释放APP胞内域(AICD)。剩余的βCTF在C-末端被截断(较长的AβS)，然后以逐步的方式(主要以三个残基间隔)顺序裁剪，以产生Aβ。有两个主要的Aβ产品线产生Aβ40和Aβ42，分别伴随着三个和两个三肽的释放。此外，还会发生许多选择性的裂解，释放含有三到六个残基的多肽。这些调节了Aβ产品线，并定义了Aβ产生的种类和数量。在这里，我们回顾了我们目前对β分泌酶对γCTF膜内切割的理解，这可能有助于未来开发一种有效的阿尔茨海默病治疗策略。
Amyloid β-protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease, the most common age-associated neurodegenerative disorder. Aβ is generated through intramembrane proteolysis of the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein (APP) by γ-secretase. The initial cleavage by γ-secretase occurs in the membrane/cytoplasm boundary of the βCTF, liberating the APP intracellular domain (AICD). The remaining βCTFs, which are truncated at the C-terminus (longer Aβs), are then cropped sequentially in a stepwise manner, predominantly at three residue intervals, to generate Aβ. There are two major Aβ product lines which generate Aβ40 and Aβ42 with concomitant release of three and two tripeptides, respectively. Additionally, many alternative cleavages occur, releasing peptides with three to six residues. These modulate the Aβ product lines and define the species and quantity of Aβ generated. Here, we review our current understanding of the intramembrane cleavage of the βCTF by γ-secretase, which may contribute to the future goal of developing an efficient therapeutic strategy for Alzheimer's disease.
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