Mechanisms of APP ectodomain function

PROJECT SUMMARY Cell membrane proteins regulate a multitude of cellular processes that are vital for organismal health. The extracellular domain is critical for ligand binding and signal transduction of the full-length receptor. In addition, approximately 2% of cell surface proteins undergo ectodomain shedding to release their extracellular domain. Ectodomain shedding may terminate the function of the full-length receptor and/or lead to the generation of either a soluble decoy receptor or an active ligand. The Amyloid Precursor Protein (APP), a type 1 membrane protein central to the etiology of Alzheimer’s disease, is one such cell surface protein that undergoes ectodomain shedding to generate various soluble APP (sAPP) fragments. Despite the known effects of the APP ectodomain on cellular and cognitive functions and the potential applications to disease, the precise molecular mechanisms mediating the function of APP ectodomain remains largely enigmatic due to the focus of the field on the Amyloid- β region of APP. Thus, the goal of the lab is to elucidate the normal physiological functions of the extracellular domain of the Amyloid Precursor Protein. Our approaches are designed to address the mechanistic gaps in knowledge by leveraging our recent discovery that sAPP functions as a ligand for the GABA type B Receptor (GABABR) and our recent identification of Phosphoglycerate Mutase Family Member 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, as a novel candidate interactor of the APP ectodomain. One line of research will elucidate the cellular responses of non-neuronal cells to sAPP and GABA B Receptor modulation, identify signaling pathways downstream of the sAPP and GABA B Receptor interaction, and determine mechanisms involved in the positive regulation of GABA B Receptor signaling by sAPP. A second line of research will investigate the cellular conditions and subcellular compartments in which APP and PGAM5 come into contact, the molecular basis of the APP and PGAM5 interaction (i.e. binding affinities, critical binding domains), and the consequences of PGAM5 on APP phosphorylation and proteolytic processing. The work in these studies will generate fundamental knowledge of the molecular mechanisms underlying the protein-protein interactions of the APP ectodomain and the cellular consequences of these interactions across different cell types.