State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, China.
J Mol Cell Biol. 2018 Oct 1;10(5):411-422. doi: 10.1093/jmcb/mjy001.
α-secretase and β-secretase are known to compete for amyloid precursor protein (APP) processing and thus play a vital role in Alzheimer's disease pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) and β-site APP cleaving enzyme 1 (BACE1) mediate the major activities of α-secretase and β-secretase in brain and share various common substrates. However, whether they function separately or together is poorly understood. Here, we show that ADAM10 and BACE1 co-localize in the neurites of mouse primary neurons. Co-immunoprecipitation and fluorescence resonance energy transfer analysis revealed that ADAM10 and BACE1 interact with each other under both endogenous and exogenous conditions. In addition, we found that ADAM10 enhances the proteolysis of neural cell adhesion molecule close homolog of L1 (CHL1) by BACE1. Further studies found that ADAM10-BACE1 interaction interfering peptide LT52 attenuates the regulation of ADAM10 on BACE1-mediated cleavage of CHL1. Our data indicate that ADAM10-BACE1 interaction regulates the proteolysis of some specific substrates and may play a potential role in brain function.
α-分泌酶和β-分泌酶已知会竞争淀粉样前体蛋白 (APP) 的加工，因此在阿尔茨海默病发病机制中发挥着至关重要的作用。解整合素金属蛋白酶 10 (ADAM10) 和β-位点 APP 裂解酶 1 (BACE1) 介导脑内 α-分泌酶和β-分泌酶的主要活性，并共享各种常见的底物。然而，它们是单独起作用还是共同起作用尚不清楚。在这里，我们显示 ADAM10 和 BACE1 在小鼠原代神经元的神经突中共定位。免疫共沉淀和荧光共振能量转移分析显示，ADAM10 和 BACE1 在内外源条件下相互作用。此外，我们发现 ADAM10 增强了 BACE1 对神经细胞黏附分子同源物 L1 (CHL1) 的蛋白水解作用。进一步的研究发现，ADAM10-BACE1 相互作用干扰肽 LT52 减弱了 ADAM10 对 BACE1 介导的 CHL1 切割的调节作用。我们的数据表明，ADAM10-BACE1 相互作用调节一些特定底物的蛋白水解，可能在大脑功能中发挥潜在作用。
