Lleó Alberto
Servicio de Neurología, Hospital de la Santa Creu i Sant Pau, Sant Antoni M Claret 167, 08025 Barcelona, Spain.
Curr Top Med Chem. 2008;8(1):9-16. doi: 10.2174/156802608783334060.
Gamma-secretase is an intramembranous protein complex that cleaves many type-I membrane proteins, including the Notch receptor and the beta-amyloid precursor protein (APP). Interest in gamma-secretase comes, in part, from the fact that this multiprotein complex is responsible for the cleavage of APP that generates the amyloid-beta peptide (Abeta), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, molecular identification of the complex has shown that gamma-secretase is an aspartyl protease composed of four different members that are essential for the enzymatic activity: presenilin 1, aph1, pen-2 and nicastrin. In recent years, an increasing number of type-I membrane proteins have been shown to be cleaved by gamma-secretase. How the enzyme cleaves such a set of substrates with diverse functions and subcellular localizations is not well understood. In overexpression assays, the gamma-secretase cleavage of some substrates releases intracellular domains with signaling properties. On the other hand, the loose specificity required for intramembrane cleavage has raised the possibility of gamma-secretase as the membrane proteasome. The impact of gamma-secretase on other substrates has clear implications for the development of new therapies for AD, and in particular for the search of gamma-secretase inhibitors or modulators. Interference with the cleavage of some of the gamma-secretase substrates has been shown to be associated with serious adverse effects in animal models. The understanding of the mechanism by which gamma-secretase recognizes and cleaves all these proteins is of great importance to clarify the function of gamma-secretase and its role as a therapeutic target in AD, and possibly in other diseases in which gamma-secretase is involved.
γ-分泌酶是一种膜内蛋白复合物，可切割多种I型膜蛋白，包括Notch受体和β-淀粉样前体蛋白（APP）。对γ-分泌酶的关注部分源于这样一个事实，即这种多蛋白复合物负责切割APP，产生淀粉样β肽（Aβ），它是阿尔茨海默病（AD）淀粉样斑块的主要成分之一。在过去几年中，对该复合物的分子鉴定表明，γ-分泌酶是一种天冬氨酸蛋白酶，由四个不同成员组成，这些成员对酶活性至关重要：早老素1、Aph1、Pen-2和尼卡斯特林。近年来，越来越多的I型膜蛋白已被证明可被γ-分泌酶切割。该酶如何切割具有不同功能和亚细胞定位的一组底物尚不清楚。在过表达实验中，γ-分泌酶对某些底物的切割会释放具有信号传导特性的细胞内结构域。另一方面，膜内切割所需的宽松特异性增加了γ-分泌酶作为膜蛋白酶体的可能性。γ-分泌酶对其他底物的影响对AD新疗法的开发具有明确意义，特别是在寻找γ-分泌酶抑制剂或调节剂方面。在动物模型中，干扰γ-分泌酶某些底物的切割已被证明与严重的不良反应有关。了解γ-分泌酶识别和切割所有这些蛋白质的机制对于阐明γ-分泌酶的功能及其作为AD治疗靶点的作用非常重要，可能在γ-分泌酶参与的其他疾病中也是如此。
