title: A lipid switch unlocks Parkinson's disease-associated ATP13A2.
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, Mn(2+), and Zn(2+) 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.
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Tine
authors.initials: T
authors.lastname: Holemans
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Danny Mollerup
authors.initials: DM
authors.lastname: Sørensen
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Sarah
authors.initials: S
authors.lastname: van Veen
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Shaun
authors.initials: S
authors.lastname: Martin
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Diane
authors.initials: D
authors.lastname: Hermans
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark;
authors.forename: Gerdi Christine
authors.identifier: http://orcid.org/0000-0002-4686-5531
authors.initials: GC
authors.lastname: Kemmer
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium; Leuven Viral Vector Core, KU Leuven, B3000 Leuven, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.affiliation: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark;
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther Pomorski
authors.affiliation: Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Frank
authors.initials: F
authors.lastname: Wuytack
authors.affiliation: Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark;
authors.forename: Michael
authors.initials: M
authors.lastname: Palmgren
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Eggermont
authors.affiliation: Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium; peter.vangheluwe@med.kuleuven.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Vangheluwe
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008345:Manganese / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D040681:Structural Homology, Protein; D015032:Zinc / Q000494:pharmacology
chemical_list: C514983:ATP13A2 protein, human; D008055:Lipids; D010712:Phosphatidic Acids; D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D049452:Green Fluorescent Proteins; D008345:Manganese; D006180:Proton-Translocating ATPases; D015032:Zinc
keywords: P5-type ATPase; flippase; lysosome; mitochondria; α-synuclein