Revealing the transport function of the mammalian P5-type ATPases

P-type transport ATPases are a large family of transport proteins that use ATP to drive the transport of a ligand from one side of a cellular membrane to the other. Of the five subfamilies (P1-5), P1-3 members represent ion or proton transporters, while P4 ATPases translocate lipids between membrane leaflets. The transport function of the five human P5-type ATPases, ATP13A1-5, is not yet established, despite their connections to diseases like Parkinson disease (ATP13A2), pulmonary arterial hypertension (ATP13A3), and autism (ATP13A4). We will use complementary biochemical assays to screen for the transported ligand of ATP13A1-5. We will investigate the mechanism of the N-terminal auto-inhibitory region in P5-type ATPases that controls their activation status and develop tools for modulating their activity. This project will lead to the elucidation of the transport function of a highly conserved orphan class of transporters that is implicated in human disease, and will generate tools to modulate their activity.