Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
Nature. 1993 Mar 4;362(6415):75-9. doi: 10.1038/362075a0.
The most characteristic change in progressive dementia of Alzheimer's type is a tissue deposit of amyloid beta/A4 protein, which is derived from its precursor protein APP (ref.2). Structural alterations of APP are implicated in the pathogenesis of Alzheimer's disease, but it is not known how they cause the disease. Although APP has a receptor-like architecture, is located on the neuronal surface, and has a conserved cytoplasmic domain, no receptor function has been demonstrated for APP. Here we report that APP forms a complex with G(o), a major GTP-binding protein in brain. The cytoplasmic APP sequence His 657-Lys 676 shows a specific G(o)-activating function and is necessary for complex formation. G(o) protein treated with GTP-gamma S lost the ability to associate with APP. This suggests that APP is a receptor coupled to G(o) and that abnormal APP-G(o) signalling is involved in the Alzheimer's disease process.
阿尔茨海默病型进行性痴呆最典型的变化是β-淀粉样蛋白/A4蛋白的组织沉积，该蛋白来源于其前体蛋白APP（参考文献2）。APP的结构改变与阿尔茨海默病的发病机制有关，但尚不清楚它们是如何引发该疾病的。尽管APP具有类似受体的结构，位于神经元表面，且具有保守的胞质结构域，但尚未证明APP具有受体功能。在此，我们报告APP与G(o)形成复合物，G(o)是脑中一种主要的GTP结合蛋白。APP的胞质序列His 657-Lys 676具有特定的G(o)激活功能，是复合物形成所必需的。用GTP-γS处理的G(o)蛋白失去了与APP结合的能力。这表明APP是一种与G(o)偶联的受体，异常的APP-G(o)信号传导参与了阿尔茨海默病的发病过程。
