Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2

Abstract

Mutations in ATP13A2, also known as PARK9, cause a rare monogenic form of juvenile onset Parkinsons disease named Kufor-Rakeb syndrome and other neurodegenerative diseases. ATP13A2 encodes a neuroprotective P5B P-type ATPase highly enriched in the brain that mediates selective import of spermine ions from lysosomes into the cytosol via an unknown mechanism. Here we present three structures of human ATP13A2 bound to an ATP analogue or to spermine in the presence of phosphomimetics determined by electron cryo-microscopy. ATP13A2 autophosphorylation opens a lysosome luminal gate to reveal a narrow lumen access channel that holds a spermine ion in its entrance. ATP13A2s architecture establishes physical principles underlying selective polyamine transport and anticipates a "pump-channel" intermediate that could function as a counter-cation conduit to facilitate lysosome acidification. Our findings establish a firm foundation to understand ATP13A2 mutations associated with disease and bring us closer to realizing ATP13A2s potential in neuroprotective therapy. HighlightsO_LIStructures of the Parkinsons disease-associated polyamine transporter ATP13A2 C_LIO_LIStructures of three transport cycle intermediates reveal the gating mechanism C_LIO_LIArchitecture of the polyamine binding site reveals mechanisms for ion selectivity C_LIO_LIThe polyamine binding sites location anticipates an ion channel-like mechanism C_LI