TY  - JOUR
A1  - Lambert, Elisabeth
A1  - Mehdipour, Ahmad Reza
A1  - Schmidt, Alexander
A1  - Hummer, Gerhard
A1  - Pérez, Camilo
T1  - Evidence for a 'trap-and-flip' mechanism in a proton-dependent lipid transporter
T2  - Nature Communications
N2  - 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.
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73519
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-735192
SN  - 2041-1723
VL  - 13
IS  - Article number 1022
PB  - Nature Publishing Group UK
CY  - London
ER  -