Abstract

Receptor ectodomain shedding is a fundamental and tightly regulated process in cell biology. It is a rapid and irreversible post-translational modification, which can have either profound positive or negative effects on cellular signalling and whole-body homeostasis. The enzymes responsible, referred to as sheddases, regulate the levels and function of hundreds of membrane proteins. As such these enzymes act as switches to regulate diverse processes including signalling and cell adhesion. Additionally, dysregulation of ectodomain shedding is associated with a wide range of pathologies, including autoimmune and cardiovascular diseases, neurodegeneration, infection and cancer. Therefore, understanding the function and regulation of these sheddases is extremely important for cell physiology and pathology. BACE1 is one of only a handful of sheddase enzymes and is sensitive to a number of physiological stimuli, including hypoxia, nutrient levels and blood flow. Therefore, we hypothesise that BACE1 is a stress-sensing sheddase and acts to regulate many cellular responses. To test this hypothesis, we will establish the BACE1 interactome and identify novel substrates using multiple unbiased proteomic approaches. This will significantly develop our understanding of BACE1 and the cellular process it is involved with. To explore the mechanism(s) involved we will perform post translational modification mapping and cellular imaging to establish how physiological stimuli can affect BACE1 activity, cellular localisation and substrate selection. Finally, we will determine the effect of BACE1 post translational modifications on cellular physiology including cell signalling and metabolism, blood vessel formation and mechanosensing. This multi-disciplinary project will lead to new insights in the role and regulation of BACE1. This project will establish a role for BACE1 in normal physiology and could lead to targeting its regulation being a novel means to maintain health.