Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Autor(en): Dadsena, Shashank
Bockelmann, Svenja 
Mina, John G. M.
Hassan, Dina G.
Korneev, Sergei 
Razzera, Guilherme
Jahn, Helene
Niekamp, Patrick
Mueller, Dagmar
Schneider, Markus
Tafesse, Fikadu G.
Marrink, Siewert J.
Melo, Manuel N.
Holthuis, Joost C. M.
Stichwörter: BAX; CELL-DEATH; DEPENDENT ANION CHANNEL-1; EFFICIENT; INHIBITION; MEMBRANE; Multidisciplinary Sciences; PROTEINS; RADIATION-INDUCED APOPTOSIS; Science & Technology - Other Topics; SPHINGOLIPID METABOLISM; TRANSPORT
Erscheinungsdatum: 2019
Herausgeber: NATURE PUBLISHING GROUP
Journal: NATURE COMMUNICATIONS
Volumen: 10
Zusammenfassung: 
Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity.
ISSN: 20411723
DOI: 10.1038/s41467-019-09654-4

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