He Wanxia, Hu Xiangyou, Shi Qi, Zhou Xiangdong, Lu Yifeng, Fisher Christopher, Yan Riqiang
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
J Mol Biol. 2006 Oct 27;363(3):625-34. doi: 10.1016/j.jmb.2006.07.094. Epub 2006 Aug 11.
BACE1 is a membrane-bound aspartyl protease that specifically cleaves amyloid precursor protein (APP) at the beta-secretase site. Membrane bound reticulon (RTN) family proteins interact with BACE1 and negatively modulate BACE1 activity through preventing access of BACE1 to its cellular APP substrate. Here, we focused our study on RTN3 and further show that a C-terminal QID triplet conserved among mammalian RTN members is required for the binding of RTN to BACE1. Although RTN3 can form homo- or heterodimers in cells, BACE1 mainly binds to the RTN monomer and disruption of the QID triplet does not interfere with the dimerization. Correspondingly, the C-terminal region of BACE1 is required for the binding of BACE1 to RTNs. Furthermore, we show that the negative modulation of BACE1 by RTN3 relies on the binding of RTN3 to BACE1. The knowledge from this study may potentially guide discovery of small molecules that can mimic the effect of RTN3 on the inhibition of BACE1 activity.
β-分泌酶1（BACE1）是一种膜结合天冬氨酸蛋白酶，它在β-分泌酶位点特异性切割淀粉样前体蛋白（APP）。膜结合网状蛋白（RTN）家族蛋白与BACE1相互作用，并通过阻止BACE1接近其细胞内APP底物来负向调节BACE1活性。在此，我们将研究重点放在RTN3上，并进一步表明，哺乳动物RTN成员中保守的C末端QID三联体是RTN与BACE1结合所必需的。虽然RTN3可在细胞中形成同二聚体或异二聚体，但BACE1主要与RTN单体结合，且QID三联体的破坏并不干扰二聚化。相应地，BACE1的C末端区域是BACE1与RTN结合所必需的。此外，我们表明RTN3对BACE1的负向调节依赖于RTN3与BACE1的结合。这项研究所得出的知识可能会潜在地指导能够模拟RTN3对BACE1活性抑制作用的小分子的发现。
