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Title: Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE

Abstract

We report that EmrE is a small, homodimeric membrane transporter that exploits the established electrochemical proton gradient across the Escherichia coli inner membrane to export toxic polyaromatic cations, prototypical of the wider small-multidrug resistance transporter family. While prior studies have established many fundamental aspects of the specificity and rate of substrate transport in EmrE, low resolution of available structures has hampered identification of the transport coupling mechanism. Here we present a complete, refined atomic structure of EmrE optimized against available cryo-electron microscopy (cryo-EM) data to delineate the critical interactions by which EmrE regulates its conformation during the transport process. With the model, we conduct molecular dynamics simulations of the transporter in explicit membranes to probe EmrE dynamics under different substrate loading and conformational states, representing different intermediates in the transport cycle. The refined model is stable under extended simulation. The water dynamics in simulation indicate that the hydrogen-bonding networks around a pair of solvent-exposed glutamate residues (E14) depend on the loading state of EmrE. One specific hydrogen bond from a tyrosine (Y60) on one monomer to a glutamate (E14) on the opposite monomer is especially critical, as it locks the protein conformation when the glutamate is deprotonated. The hydrogen bondmore » provided by Y60 lowers the pK a of one glutamate relative to the other, suggesting both glutamates should be protonated for the hydrogen bond to break and a substrate-free transition to take place. In conclusion, these findings establish the molecular mechanism for the coupling between proton transfer reactions and protein conformation in this proton-coupled secondary transporter.« less

Authors:
ORCiD logo; ; ORCiD logo
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1460924
Alternate Identifier(s):
OSTI ID: 1485839
Report Number(s):
SAND-2018-12663J
Journal ID: ISSN 0027-8424; /pnas/115/32/E7502.atom
Grant/Contract Number:  
AC52-06NA25296; AC04-94AL85000; NA0003525
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 32; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; molecular dynamics; membrane protein; structure refinement; proton-coupled transport

Citation Formats

Vermaas, Josh V., Rempe, Susan B., and Tajkhorshid, Emad. Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE. United States: N. p., 2018. Web. doi:10.1073/pnas.1722399115.
Vermaas, Josh V., Rempe, Susan B., & Tajkhorshid, Emad. Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE. United States. doi:10.1073/pnas.1722399115.
Vermaas, Josh V., Rempe, Susan B., and Tajkhorshid, Emad. Thu . "Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE". United States. doi:10.1073/pnas.1722399115.
@article{osti_1460924,
title = {Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE},
author = {Vermaas, Josh V. and Rempe, Susan B. and Tajkhorshid, Emad},
abstractNote = {We report that EmrE is a small, homodimeric membrane transporter that exploits the established electrochemical proton gradient across the Escherichia coli inner membrane to export toxic polyaromatic cations, prototypical of the wider small-multidrug resistance transporter family. While prior studies have established many fundamental aspects of the specificity and rate of substrate transport in EmrE, low resolution of available structures has hampered identification of the transport coupling mechanism. Here we present a complete, refined atomic structure of EmrE optimized against available cryo-electron microscopy (cryo-EM) data to delineate the critical interactions by which EmrE regulates its conformation during the transport process. With the model, we conduct molecular dynamics simulations of the transporter in explicit membranes to probe EmrE dynamics under different substrate loading and conformational states, representing different intermediates in the transport cycle. The refined model is stable under extended simulation. The water dynamics in simulation indicate that the hydrogen-bonding networks around a pair of solvent-exposed glutamate residues (E14) depend on the loading state of EmrE. One specific hydrogen bond from a tyrosine (Y60) on one monomer to a glutamate (E14) on the opposite monomer is especially critical, as it locks the protein conformation when the glutamate is deprotonated. The hydrogen bond provided by Y60 lowers the pKa of one glutamate relative to the other, suggesting both glutamates should be protonated for the hydrogen bond to break and a substrate-free transition to take place. In conclusion, these findings establish the molecular mechanism for the coupling between proton transfer reactions and protein conformation in this proton-coupled secondary transporter.},
doi = {10.1073/pnas.1722399115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 32,
volume = 115,
place = {United States},
year = {2018},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1073/pnas.1722399115

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Cited by: 4 works
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Figures / Tables:

Fig. 1 Fig. 1: Schematic of the transport cycle of EmrE following the alternating access mechanism with a strict 2:1 H+:TPP+ stoichiometry. EmrE monomers (red and blue ellipsoids) swap conformations (schematically indicated by the size and angle of the ellipse relative to the membrane) and thus alternate the substrate/proton accessibility to themore » inside or outside of the cell when loaded with protons (Left) or substrate (Right). When the EmrE dimer is in its apo (Center) form, the transition should be forbidden (red dashed arrow) to preserve the coupling of proton and substrate transport and prevent proton leakage across the membrane. This apo state is in contrast to both the fully protonated and substrate-bound states (Left and Right columns, respectively), whose transition should be allowed (black solid arrows) for EmrE to fulfill its physiological function as a proton-driven polyaromatic cation transporter.« less

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