Lipids modulate the conformational dynamics of a secondary multidrug transporter
Chloe Martens,Richard A. Stein,Matthieu Masureel,Aurélie Roth,Smriti Mishra,Rosie Dawaliby,Albert Konijnenberg,Frank Sobott,Cédric Govaerts,Hassane S. Mchaourab +9 more
TLDR
The model emerging from the 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.Abstract:
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.read more
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Multidrug efflux pumps: structure, function and regulation
Dijun Du,Xuan Wang-Kan,Arthur Neuberger,Hendrik W. van Veen,Klaas M. Pos,Laura J. V. Piddock,Ben F. Luisi +6 more
TL;DR: Recent advances that have increased understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria are described, suggesting opportunities for countering their activities.
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Nanodiscs in Membrane Biochemistry and Biophysics
TL;DR: This review attempted to combine a comprehensive list of various applications of nanodisc technology with systematic analysis of the most attractive features of this system and advantages provided by nanodISCs for structural and mechanistic studies of membrane proteins.
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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).
TL;DR: The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters as discussed by the authors, which is responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients.
Journal ArticleDOI
Direct protein-lipid interactions shape the conformational landscape of secondary transporters
Chloe Martens,Mrinal Shekhar,Antoni J. Borysik,Andy M. Lau,Eamonn Reading,Emad Tajkhorshid,Paula J. Booth,Argyris Politis +7 more
TL;DR: Hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations are used to understand how lipids regulate the conformational dynamics of secondary transporters and reveal that conserved networks of charged residues act as molecular switches that drive the conformular transition between different states.
Journal ArticleDOI
Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer
Suraj Adhikary,Daniel Deredge,Anu Nagarajan,Lucy R. Forrest,Patrick L. Wintrode,Satinder K. Singh +5 more
TL;DR: The reconstituted prokaryotic homolog LeuT into nanodiscs and subjected the preparation to hydrogen–deuterium exchange mass spectrometry to reveal a global view of the hallmarks of the transporter in two disparate conformations, illuminating the value of this strategy for interrogating the conformational mechanism of the more clinically significant mammalian membrane proteins including SERT and DAT.
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