Mechanism of substrate selectivity of gamma-secretase regulated by membrane trafficking

γ-分泌酶是一种膜包埋的蛋白酶，负责在AD患者脑内积聚产生致病的A-β多肽，因此被认为是治疗AD的有前途的药物靶点。γ-分泌酶具有多种底物，因此了解其底物选择性的分子机制是至关重要的。为此，我们已经确定了专门调控Notch受体贩运的Surf4。Surf4识别Notch受体的胞浆部分，并将其招募到内质网出口部位，并调节其内质网到高尔基体的运输。

γ-Secretase is a membrane embedded protease responsible for the production of pathogenic Aβpeptide accumulated in the brains of AD patient, therefore it has been regarded as a promising druggable target for the treatment of AD.γ-Secretase has a number of substrates, so it is crucial to understand its molecular mechanism of substrate selectivety. To this end, we have identified Surf4 that specifically regulates Notch receptor trafficking. Surf4 recognizes the cytosolic portion of Notch receptor and recruits it to the ER-exit site, and regulate its ER-to-Golgi trafficking.