Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

Lambert, Elisabeth and Mehdipour, Ahmad Reza and Schmidt, Alex and Hummer, Gerhard and Perez, Camilo. (2022) Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter. Nature Communications, 13. 1022 .

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Official URL: https://edoc.unibas.ch/84206/

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Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters participate in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acids synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a trap-and-flip mechanism that might be shared among MFS lipid transporters.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Perez)
UniBasel Contributors:Lambert, Elisabeth and Schmidt, Alexander and Perez, Camilo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Mar 2022 07:41
Deposited On:14 Feb 2022 09:50

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