Abstracts
Molecular mechanism of ceramide transfer by STARD11 / CERT
Molecular mechanism of ceramide transfer by STARD11 / CERT : an in vitro study
Presenting author: Camille Cuveillier
University of Geneva, Physiology and metabolism, 1 rue Michel Servet, 1206 Geneva [CH], camille.cuveillier@unige.ch
Author(s):
Camille Cuveillier, Mahmoud Moqadam, Nathalie Reuter, Anne-Claude Gavin
Non-vesicular lipid transport by lipid transfer proteins (LTPs) is crucial for establishing and maintaining membrane lipid composition. LTPs shield lipids from the aqueous environment and mediate their uptake and release at membrane surfaces. These opposing steps are energetically demanding, as they require moving lipids across the hydrophilic headgroup region without external energy input. Taking STARD11 lipid transfer domain as a model, we combined molecular dynamic simulation and in vitro lipid transfer assays to uncover the central role of a conserved arginine in Ω1 loop. This residue provides structure to the gate of the lipid-binding cavity via an H-bond network and fine-tune the opening of the gate by interacting with membrane phospholipid phosphate groups leading to fast ceramide uptake. Finally, using bifunctional lipids, we show that the opening of the protein modifies membrane properties by promoting lipid fatty acid snorkeling. Overall, our findings reveal a bidirectional coupling in which the conserved Ω1-loop arginine enables STARD11 to reshape local membrane structure while membrane phospholipids reciprocally stabilize gate opening, together driving efficient lipid transport.
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Molecular Mechanism of Ceramide Transfer by STARD11 / CERT: A Molecular Dynamics Investigation
Presenting author: Mahmoud Moqadam
University of Bergen, Chemistry, Bregnestien 8B, 5141 Fyllingsdalen [NO], mahmoud.moqadam@uib.no
Author(s):
Mahmoud Moqadam, Camille Cuveillier, Anne-Claude Gavin, Nathalie Reuter
Non-vesicular lipid transport by lipid transfer proteins (LTPs) is crucial for regulating cellular lipid distribution and maintaining membrane composition. A defining feature of all LTPs is their ability to shield lipids within a hydrophobic cavity, reducing the energetic cost of transfer relative to the aqueous environment. A fundamental yet unresolved question is the mechanism by which LTPs coordinate membrane binding and gate opening with lipid uptake and release. Using the ceramide transporter STARD11 as a model system, we performed molecular dynamics simulations to dissect the membrane-dependent gating mechanism. We show that an arginine located in the Ω1 loop and conserved in 14 of the 15 human START domains plays a critical dual role: it maintains the structural integrity of the gate, and strongly interacts with a membrane phospholipid that promotes and sustains gate opening. This opening disrupts local membrane lipid packing and increases lipid tail snorkeling toward the open cavity. Using in vitro lipid transfer assays of the wild-type STARD11 and mutants, we show that mutating the arginine decreases the rate of ceramide uptake. Overall, our findings reveal a functional role for conserved arginine and highlight a mechanistic coupling between membrane lipid dynamics and cavity accessibility that together drives efficient lipid transport by the START domain protein.