Molecular mechanisms of low-density lipoprotein receptor regulation by the protease BMP1

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Cholesterol homeostasis in mammals is tightly controlled by its biosynthesis, dietary intake and cellular uptake from the blood. The low-density lipoprotein receptor (LDLR) is responsible for the cellular uptake of cholesterol in the form of low-density lipoprotein cholesterol (LDL-C). At the surface of hepatocytes and other cells, LDLR binds LDL-C and the complex is then internalized by receptor-mediated endocytosis. The activity of LDLR is tightly regulated through its biosynthesis, surface localisation, internalisation, recycling and degradation, in order to maintain cellular cholesterol homeostasis. Recently we have identified that LDLR is proteolytically cleaved at a physiologically-relevant site within its ligand-binding domain by the zinc metalloprotease bone morphogenetic protein 1 (BMP1) (Banerjee et al. 2019). The cleavage of LDLR by BMP1 reduces the binding and endocytosis of LDL-C. Thus proteolytic cleavage of LDLR by BMP1 is a new mechanism to regulate cellular LDL-C uptake. We hypothesise that molecular interactions between BMP1, LDLR and other cellular components regulate the proteolytic cleavage of LDLR by BMP1 and impact on LDL-C metabolism. To address this hypothesis, the objectives of this proposal are to: 1) determine the role of the non-catalytic protein-protein interaction domains on BMP1 in the recognition and cleavage of LDLR; and 2) identify the proteins that bind BMP1 or LDLR to regulate the proteolytic cleavage of LDLR by BMP1 and hence LDL-C endocytosis. This is a curiosity-driven bioscience project that will provide new understanding of the biological mechanisms controlling the cellular uptake of cholesterol and could lead to new molecular targets to modulate low-density lipoprotein receptor (LDLR) action and manage cholesterol homeostasis. Thus, the project addresses the BBSRC priority areas of "Understanding the rules of life" within the "Advancing the frontiers of bioscience discovery" theme.