T. Holemans, D.M. Sørensen, S. van Veen, S. Martin, D. Hermans, G.C. Kemmer, C. van den Haute, V. Baekelandt, T. Günther Pomorski, P. Agostinis, F. Wuytack, M. Palmgren, J. Eggermont, and P. Vangheluwe (2015).
A lipid switch unlocks Parkinson’s disease-associated ATP13A2.
Proceedings of the National Academy of Sciences (USA) 112(29): 9040–9045.
doi: 10.1073/pnas.1508220112
Abstract
ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor–Rakeb syndrome and Parkinson’s disease (PD), providing protection against α-synuclein, Mn2+, and Zn2+ toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2]. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5)P2. Thus, the N-terminal binding of PA and PI(3,5)P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce α-synuclein toxicity or mitochondrial stress in PD or related disorders.