Cited by 24Drug Transport and Resistance MechanismsLipid Membrane Structure and BehaviorProtein Structure and Dynamics

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

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Lambert, Elisabeth, Mehdipour, Ahmad Reza, Schmidt, Alexander, Hummer, Gerhard, Perez, Camilo·2022·Nature Communications

Published version of a preprint

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.

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Authors
Lambert, E., Mehdipour, A. R., Schmidt, A., Hummer, G., & Perez, C.
Affiliations
  • University of Basel (CH)
  • Ghent University (BE)
  • Goethe University Frankfurt (DE)
Venue
Nature Communications
Published
2022-02-23
Volume
13
Issue
1
Pages
1022-1022
ISSN
2041-1723 (ISSN-L)
OpenAlex
W4220660898
Cited by
24
References
83
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 1
FWCI
2.20
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • edoc (University of Basel) (acceptedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_198903)
  • Deutsche Forschungsgemeinschaft (SFB 807)
  • Max-Planck-Gesellschaft
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
major facilitator superfamily, lipid transfer proteins, Staphylococcus aureus, substrate specificity, lipid translocation
MeSH terms
Biological Transport, Lipids, Protein Conformation, Protons, Membrane Transport Proteins, Molecular Dynamics Simulation

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