VIB Center for the Biology of Disease, VIB, B-3000 Leuven, Belgium.
J Cell Sci. 2013 Nov 1;126(Pt 21):4856-61. doi: 10.1242/jcs.137919. Epub 2013 Aug 28.
Proteolytic processing of amyloid-β precursor protein (APP) generates the amyloid-β peptide, which plays a central role in Alzheimer disease. The physiological function of APP and its proteolytic fragments, however, remains barely understood. Here we show that, on the basis of its binding characteristics, the secreted ectodomain of APP (sAPP) is a new member of the heparin-binding growth factor superfamily. Like other of its members, sAPP binds in a bivalent manner to the plasma membrane with two different subdomains. The N-terminal growth-factor-like domain (GFLD) is necessary and sufficient for protein-receptor binding, whereas the E2-domain mediates interaction with membrane-anchored heparan sulfate proteoglycans (HSPGs). The membrane-anchored HSPGs function as low-affinity co-receptors for sAPP and enhance the affinity to the sAPP receptor. Our findings provide a solid basis for the further identification of this receptor.
淀粉样蛋白-β前体蛋白（APP）的蛋白水解加工产生淀粉样蛋白-β肽，该肽在阿尔茨海默病中起核心作用。然而，APP 及其蛋白水解片段的生理功能仍知之甚少。在这里，我们表明，根据其结合特性，APP 的分泌型胞外结构域（sAPP）是肝素结合生长因子超家族的新成员。像其他成员一样，sAPP 以二价方式与细胞膜结合，具有两个不同的亚结构域。N 端生长因子样结构域（GFLD）是蛋白-受体结合所必需和充分的，而 E2 结构域介导与膜锚定的硫酸乙酰肝素蛋白聚糖（HSPGs）的相互作用。膜锚定的 HSPGs 作为 sAPP 的低亲和力共受体，增强了与 sAPP 受体的亲和力。我们的发现为进一步鉴定该受体提供了坚实的基础。
