Year: 2019
Type: article
Abstract: 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.
Source: Nature Communications
Institutions: Osnabrück University, Teesside University, Ain Shams University, Universidade Federal de Santa Catarina, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oregon Health & Science University, University of Groningen, Zernike Institute for Advanced Materials, Utrecht University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G105728699, G1516346500, G3749336523, Sphingolipid homeostasis: from basic biology to applications, G3891694003, G449056522, G5468631136, Defining the role of host lipid repertoire in Mycobacterium tuberculosis infection, G5647034220, Determining the role of sphingolipids in Mycobacterium tuberculosis infection, G946021960
OpenAlex ID: W2940888331