Ceramides bind VDAC2 to trigger mitochondrial apoptosis
| Autor: | Dina G Hassan, Dagmar Müller, Patrick Niekamp, Siewert J. Marrink, Shashank Dadsena, Guilherme Razzera, Markus Schneider, Sergei Korneev, Manuel N. Melo, Joost C. M. Holthuis, John G. Mina, Helene Jahn, Svenja Bockelmann, Fikadu G. Tafesse |
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| Přispěvatelé: | Molecular Dynamics, Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Molecular, Structural and Cellular Microbiology (MOSTMICRO) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chemistry(all) Ceramide binding General Physics and Astronomy EFFICIENT 02 engineering and technology Mitochondrion Gene Knockout Techniques chemistry.chemical_compound RADIATION-INDUCED APOPTOSIS RNA Small Interfering lcsh:Science Multidisciplinary SPHINGOLIPID METABOLISM Effector Chemistry apoptosis 021001 nanoscience & nanotechnology Recombinant Proteins 3. Good health Cell biology mitochondria VDAC2 0210 nano-technology VDAC1 Programmed cell death Ceramide PROTEINS Science INHIBITION Glutamic Acid Physics and Astronomy(all) Molecular Dynamics Simulation Ceramides Article General Biochemistry Genetics and Molecular Biology Computational biophysics 03 medical and health sciences DEPENDENT ANION CHANNEL-1 SDG 3 - Good Health and Well-being Humans Sphingolipids Binding Sites Biochemistry Genetics and Molecular Biology(all) Voltage-Dependent Anion Channel 2 Voltage-Dependent Anion Channel 1 HEK 293 cells General Chemistry HCT116 Cells TRANSPORT HEK293 Cells 030104 developmental biology CELL-DEATH BAX lcsh:Q MEMBRANE Chemical tools HeLa Cells Coarse-grain molecular dynamics simulations |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) Nature Communications, 10(1):1832. Nature Publishing Group Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-09654-4 |
| Popis: | 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. Ceramides are lipids that act directly on mitochondria to trigger apoptosis, but the underlying mechanism remains largely unclear. Here authors use a photoactivatable ceramide probe combined with a computation approach and functional studies to identify the voltage-dependent anion channel VDAC2 as a direct effector of ceramide-mediated cell death. |
| Databáze: | OpenAIRE |
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