Direct protein-lipid interactions shape the conformational landscape of secondary transporters
By Chloé Martens, M. Shekhar, A. Borysik, Andy M. Lau, Eamonn Reading, Emad Tajkhorshid, P. Booth, Argyris Politis. 2018
129 citations recorded by the source corpus.
Secondary transporters undergo structural rearrangements to catalyze substrate translocation across the cell membrane – yet how such conformational changes happen within a lipid environment remains poorly understood. Here, we combine hydrogen-deuterium exchange mass spectrometry (HDX-MS) with molecular dynamics (MD) simulations to understand how lipids regulate the conformational dynamics of secondary transporters at the molecular level. Using the homologous transporters XylE, LacY and GlpT from Escherichia coli as model systems, we discover that conserved networks of charged residues act as molecular switches that drive the conformational transition between different states. We reveal that these molecular switches are regulated by interactions with surrounding phospholipids and show that phosphatidylethanolamine interferes with the formation of the conserved networks and favors an inward-facing state. Overall, this work provides insights into the importance of lipids in shaping the conformational landscape of an important class of transporters. Secondary transporters catalyse substrate translocation across the cell membrane but the role of lipids during the transport cycle remains unclear. Here authors used hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations to understand how lipids regulate the conformational dynamics of secondary transporters.
Subfields: Molecular Biology, Oncology
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In Molecular Biology
- Gerhard Hummer
- Diego del Alamo
- Jens Meiler
- Davide Sala
- Hassane S. Mchaourab
- Björn Wallner
- David Baker
In Oncology
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 ).”
- Inward-facing conformation of a multidrug resistance MATE family transporter (2019, background): “(28) recently proposed a model for the lipid-induced conformational equilibrium of secondary active transporters based on hydrogen/ deuterium exchange mass spectrometry and MD simulation experiments.”