J Biol Chem. 2014 Jul 25;289(30):20630-7. doi: 10.1074/jbc.M114.579862.
BACE1 is a type I transmembrane aspartyl protease that cleaves amyloid precursor protein at the β-secretase site to initiate the release of β-amyloid peptide. As a secretase, BACE1 also cleaves additional membrane-bound molecules by exerting various cellular functions. In this study, we showed that BACE1 can effectively shed the membrane-anchored signaling molecule Jagged 1 (Jag1).Wealso mapped the cleavage sites of Jag1 by ADAM10 and ADAM17. Although Jag1 shares a high degree of homology with Jag2 in the ectodomain region, BACE1 fails to cleave Jag2 effectively, indicating a selective cleavage of Jag1. Abolished cleavage of Jag1 in BACE1-null mice leads to enhanced astrogenesis and, concomitantly, reduced neurogenesis. This characterization provides biochemical evidence that the Jag1-Notch pathway is under the control of BACE1 activity
BACE1 是一种 I 型跨膜天冬氨酸蛋白酶，可在 β-分泌酶位点切割淀粉样前体蛋白，从而启动 β-淀粉样肽的释放。作为一种分泌酶，BACE1 通过发挥各种细胞功能还可切割其他膜结合分子。在这项研究中，我们表明 BACE1 可以有效地切割膜锚定的信号分子 Jagged 1（Jag1）。我们还通过 ADAM10 和 ADAM17 对 Jag1 的切割位点进行了定位。尽管 Jag1 在其细胞外结构域区域与 Jag2 具有高度同源性，但 BACE1 不能有效地切割 Jag2，表明 Jag1 的选择性切割。BACE1 缺失型小鼠中 Jag1 的切割缺失导致星形胶质细胞增生增强，同时神经发生减少。这一特征为 Jag1-Notch 通路受 BACE1 活性控制提供了生化证据。
