Lipid-Dependent Alternating Access Mechanism of a Bacterial Multidrug ABC Exporter
By Kalyan Immadisetty, J. Hettige, Mahmoud Moradi. 2019
36 citations recorded by the source corpus.
By undergoing conformational changes, active membrane transporters alternate between an inward-facing (IF) and an outward-facing (OF) state to transport their substrates across cellular membrane. The conformational landscape of membrane transporters, however, could be influenced by their environment, and the dependence of the alternating access mechanism on the lipid composition has not been understood at the molecular level. We have performed an extensive set of microsecond-level all-atom molecular dynamics (MD) simulations on bacterial ATP binding cassette (ABC) exporter Sav1866 in six different phosphocholine (PC) and phosphoethanolamine (PE) lipid membrane environments. This study mainly focuses on the energetically downhill OF-to-IF conformational transition of Sav1866 upon the ATP hydrolysis. We observe that the transporter undergoes large-scale conformational changes in the PE environment, particularly in the POPE lipids, resulting in an IF-occluded conformation, a transition that does not occur when the transporter is embedded in any of the PC lipid bilayers. We propose that the PE lipids facilitate the closing of the protein on the periplasmic side due to their highly polar headgroups that mediate the interaction of the two transmembrane (TM) bundles by a network of lipid–lipid and lipid–protein hydrogen bonds. POPE lipids in particular facilitate the closure of periplasmic gate by promoting a hinge formation in TM helices and an interbundle salt bridge formation. This study explains how the alternating access mechanism and the flippase activity in ABC exporters could be lipid-dependent.
Subfields: Genetics, Molecular Medicine, Oncology
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Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, background): “Moreover, AF2 does not directly account for the lipid environment, which has been experimentally shown to bias the conformational equilibria of membrane proteins ( Martens et al., 2018 ; Muller et al., 2019 ; Immadisetty et al., 2019 ).”