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

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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.