Finding the trigger to apoptosis

Oeiras, 29.04.2019

In eukaryotic cell membranes ceramides are lipids that, beyond a structural aspect, also participate in cellular processes, including controlling signaling molecules in response to physiological cues and stresses. Ceramides are central intermediates in sphingolipid metabolism and were also known to have a key role in mediating antiproliferative and tumor suppressive processes. The molecular mechanism that underlined this antiproliferative action was not clear, but now Manuel Melo Lab in collaboration with colleagues from the Netherlands and Germany have identified one of the ways by which ceramides act. The results were published in Nature Communications.

The teams at the Joost Holthuis Lab, University of Osnabrück, Germany, and the John Mina Lab, Teeside University, UK, were able to experimentally identify the voltage-dependent anion channels that act as mitochondrial ceramide binding proteins. Complementary, at the Manuel Melo Lab, ITQB NOVA, Portugal, and at the Siewert Marrink Lab, University of Groningen, The Netherlands, the ceramide binding site was identified and characterized using a coarse-grain modeling approach — in which molecular representations are simplified to allow the simulation of large systems for long enough time. These findings were then confirmed experimentally after the modeling teams proposed protein mutations that were computationally predicted to abolish ceramide binding.

"This work allowed us to confirm the direct role ceramide has in apoptosis, and to put forth, demonstrate and validate a mechanism that was not known until now", explained Manuel Melo, principal investigator at the ITQB NOVA Multiscale Modeling Lab and co-corresponding author. "This joint approach also validates coarse-grain molecular modeling not only as an important tool to clarify molecular mechanisms of action but also as a valid source of new hypotheses to test experimentally."

Original article

Nature Communications April 2019 doi.org/10.1038/s41467-019-09654-4
Ceramides bind VDAC2 to trigger mitochondrial apoptosis
Shashank Dadsena, Svenja Bockelmann, John G.M. Mina*, Dina G. Hassan, Sergei Korneev, Guilherme Razzera, Helene Jahn, Patrick Niekamp, Dagmar Müller, Markus Schneider, Fikadu G. Tafesse, Siewert J. Marrink, Manuel N. Melo* & Joost C.M. Holthuis*

*corresponding authors