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

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Abstract
LtaA catalyzes glycolipid translocation by a 'trap-and-flip' mechanism, pointing to a shared mechanistic model among MFS lipid transporters. Asymmetric lateral openings allow access of the entire lipid substrate to the amphipathic central cavity. 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.
Keywords
MAJOR FACILITATOR SUPERFAMILY, LIPOTEICHOIC ACID, MOLECULAR-DYNAMICS, CRYSTAL-STRUCTURE, ESCHERICHIA-COLI, MFSD2A, BIOSYNTHESIS, RECOGNITION, VALIDATION, ZEBRAFISH

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MLA
Lambert, Elisabeth, et al. “Evidence for a Trap-and-Flip Mechanism in a Proton-Dependent Lipid Transporter.” NATURE COMMUNICATIONS, vol. 13, no. 1, 2022, doi:10.1038/s41467-022-28361-1.
APA
Lambert, E., Mehdipour, A., Schmidt, A., Hummer, G., & Perez, C. (2022). Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter. NATURE COMMUNICATIONS, 13(1). https://doi.org/10.1038/s41467-022-28361-1
Chicago author-date
Lambert, Elisabeth, Ahmadreza Mehdipour, Alexander Schmidt, Gerhard Hummer, and Camilo Perez. 2022. “Evidence for a Trap-and-Flip Mechanism in a Proton-Dependent Lipid Transporter.” NATURE COMMUNICATIONS 13 (1). https://doi.org/10.1038/s41467-022-28361-1.
Chicago author-date (all authors)
Lambert, Elisabeth, Ahmadreza Mehdipour, Alexander Schmidt, Gerhard Hummer, and Camilo Perez. 2022. “Evidence for a Trap-and-Flip Mechanism in a Proton-Dependent Lipid Transporter.” NATURE COMMUNICATIONS 13 (1). doi:10.1038/s41467-022-28361-1.
Vancouver
1.
Lambert E, Mehdipour A, Schmidt A, Hummer G, Perez C. Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter. NATURE COMMUNICATIONS. 2022;13(1).
IEEE
[1]
E. Lambert, A. Mehdipour, A. Schmidt, G. Hummer, and C. Perez, “Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter,” NATURE COMMUNICATIONS, vol. 13, no. 1, 2022.
@article{8749037,
  abstract     = {{LtaA catalyzes glycolipid translocation by a 'trap-and-flip' mechanism, pointing to a shared mechanistic model among MFS lipid transporters. Asymmetric lateral openings allow access of the entire lipid substrate to the amphipathic central cavity. 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.}},
  articleno    = {{1022}},
  author       = {{Lambert, Elisabeth and Mehdipour, Ahmadreza and Schmidt, Alexander and Hummer, Gerhard and Perez, Camilo}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{MAJOR FACILITATOR SUPERFAMILY,LIPOTEICHOIC ACID,MOLECULAR-DYNAMICS,CRYSTAL-STRUCTURE,ESCHERICHIA-COLI,MFSD2A,BIOSYNTHESIS,RECOGNITION,VALIDATION,ZEBRAFISH}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{13}},
  title        = {{Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter}},
  url          = {{http://doi.org/10.1038/s41467-022-28361-1}},
  volume       = {{13}},
  year         = {{2022}},
}

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