Lipids modulate the conformational dynamics of a secondary multidrug transporter
By Chloé Martens, Richard A. Stein, M. Masureel, Aurélie Roth, Smriti Mishra, R. Dawaliby, A. Konijnenberg, F. Sobott, C. Govaerts, Hassane S. Mchaourab. 2016
118 citations recorded by the source corpus.
Direct interactions with lipids have emerged as key determinants of the folding, structure and function of membrane proteins, but an understanding of how lipids modulate protein dynamics is still lacking. Here, we systematically explored the effects of lipids on the conformational dynamics of the proton-powered multidrug transporter LmrP from Lactococcus lactis, using the pattern of distances between spin-label pairs previously shown to report on alternating access of the protein. We uncovered, at the molecular level, how the lipid headgroups shape the conformational-energy landscape of the transporter. The model emerging from our data suggests a direct interaction between lipid headgroups and a conserved motif of charged residues that control the conformational equilibrium through an interplay of electrostatic interactions within the protein. Together, our data lay the foundation for a comprehensive model of secondary multidrug transport in lipid bilayers.
Subfields: Atomic and Molecular Physics, and Optics, Molecular Biology
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Citations in the corpus
- Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, positive): “…we found that AF2 modeled the multidrug transporter LmrP (target T1024) in multiple conformations, two of which were individually consistent with published experimental data ( Jumper et al., 2021b ; Del Alamo et al., 2021a ; Debruycker et al., 2020 ; Martens et al., 2016 ; Masureel et al., 2014 ).”
- Alternating access mechanisms of LeuT-Fold transporters: trailblazing towards the promised energy landscapes (2016, background): “Recent spectroscopic analysis of the proton-dependent multidrug transporter LmrP uncovered shifts in the free energy landscape between inward- and outward-facing conformations that were dependent on lipid headgroup interaction with a conserved chargerelay network [45].”
- AlphaFold2 predicts the inward-facing conformation of the multidrug transporter LmrP (2021, background): “Active transporters such as LmrP alternate between outward- and inward-facing conformations (OF and IF, respectively) during their transport cycles.(1-3) Whereas the crystal structure captures LmrP in the former,(4) AlphaFold2 modeled LmrP in the latter(5) (Figure 1A).”