A Membrane-Assisted Mechanism for the Release of Ceramide from the CERT START Domain

Article Article scientifique Article A Membrane-Assisted Mechanism for the Release of Ceramide from the CERT START Domain eng 2024-06-21 2024-07-04 author Moqadam Mahmoud 0000-0002-3456-5064 Department of Chemistry, University of Bergen, Bergen 5020, Norway author Gartan Parveen Department of Chemistry, University of Bergen, Bergen 5020, Norway author Talandashti Reza Department of Chemistry, University of Bergen, Bergen 5020, Norway author Chiapparino Antonella European Molecular Biology Laboratory, EMBL, Meyerhofstrasse 1, Heidelberg D-69117, Germany author Titeca Kevin 0000-0002-7677-8252 European Molecular Biology Laboratory, EMBL, Meyerhofstrasse 1, Heidelberg D-69117, Germany 944300 author Gavin Perrin Anne-Claude 0000-0003-4917-2340 Department of Cell Physiology and Metabolism, University of Geneva, CMU Rue Michel-Servet 1, Genève 4 1211, Switzerland 23293 Département de physiologie cellulaire et métabolisme (PHYME) author Reuter Nathalie 0000-0002-3649-7675 Department of Chemistry, University of Bergen, Bergen 5020, Norway 6338-6351 10.1021/acs.jpcb.4c02398 38903016 1520-5207 PMC11228987 https://pubs.acs.org/doi/10.1021/acs.jpcb.4c02398 Ceramide transfer protein CERT is the mediator of nonvesicular transfer of ceramide from the ER to Golgi. In CERT, START is the domain responsible for the binding and transport of ceramide. A wealth of structural data has revealed a helix-grip fold surrounding a large hydrophobic cavity holding the ceramide. Yet, little is known about the mechanisms by which START releases the ceramide through the polar region and into the packed environment of cellular membranes. As such events do not lend themselves easily to experimental investigations, we used multiple unbiased microsecond-long molecular simulations. We propose a membrane-assisted mechanism in which the membrane acts as an allosteric effector initiating the release of ceramide and where the passage of the ceramide acyl chains is facilitated by the intercalation of a single phosphatidylcholine lipid in the cavity, practically greasing the ceramide way out. We verify using free energy calculation and experimental lipidomics data that CERT forms stable complexes with phosphatidylcholine lipids, in addition to ceramide, thus providing validation for the proposed mechanism. Cell Membrane / chemistry Cell Membrane / metabolism Ceramides / chemistry Humans Molecular Dynamics Simulation Phosphatidylcholines / chemistry Protein Domains Protein Serine-Threonine Kinases Thermodynamics Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 1276 Métabolisme des lipides 1001 The journal of physical chemistry. B 128 26 e577043f-3937-4517-a48c-e7a340ca7e5f Article (Published version) Public jp4c02398.pdf 9380956 application/pdf CC BY-4.0 2185b3e554923a92d8ade63c4f7b3016527359ed65c80fec5b4f18b20a0b77f9 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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A Membrane-Assisted Mechanism for the Release of Ceramide from the CERT START Domain	The journal of physical chemistry. B			2024	90	45

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Titeca, Kevin