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

Elisabeth Lambert, Ahmad Reza Mehdipour, Alexander Schmidt, Gerhard Hummer and Camilo Perez ()
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Elisabeth Lambert: University of Basel
Ahmad Reza Mehdipour: Ghent University
Alexander Schmidt: University of Basel
Gerhard Hummer: Goethe University Frankfurt
Camilo Perez: University of Basel

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters take part 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 acid 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.

Date: 2022
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DOI: 10.1038/s41467-022-28361-1

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