Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states

  1. Rahul Chadda
  2. Nathan Bernhardt
  3. Elizabeth G Kelley
  4. Susana C M Teixeira
  5. Kacie Griffith
  6. Alejandro Gil-Ley
  7. Tuğba N Öztürk
  8. Lauren E Hughes
  9. Ana Forsythe
  10. Venkatramanan Krishnamani
  11. José D Faraldo-Gómez  Is a corresponding author
  12. Janice L Robertson  Is a corresponding author
  1. Washington University in St Louis, United States
  2. National Heart, Lung and Blood Institute, National Institutes of Health, United States
  3. National Institute for Standards and Technology, United States
  4. University of Delaware, United States
  5. Carver College of Medicine, The University of Iowa, United States

Abstract

Over two-thirds of integral membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 Cl-/H+ antiporter. Integrating experimental and computational approaches, we show that monomers associate to avoid a thinned-membrane defect formed by hydrophobic mismatch at their exposed dimerization interfaces. In this defect, lipids are strongly tilted and less densely packed than in the bulk, with a larger degree of entanglement between opposing leaflets and greater water penetration into the bilayer interior. Dimerization restores the membrane to a near-native state and therefore, appears to be driven by the larger free-energy cost of lipid solvation of the dissociated protomers. Supporting this theory, we demonstrate that addition of short-chain lipids strongly shifts the dimerization equilibrium towards the monomeric state, and show that the cause of this effect is that these lipids preferentially solvate the defect. Importantly, we show that this shift requires only minimal quantities of short-chain lipids, with no measurable impact on either the macroscopic physical state of the membrane or the protein's biological function. Based on these observations, we posit that free-energy differentials for local lipid solvation define membrane-protein association equilibria. With this, we argue that preferential lipid solvation is a plausible cellular mechanism for lipid regulation of oligomerization processes, as it can occur at low concentrations and does not require global changes in membrane properties.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2-6.

Article and author information

Author details

  1. Rahul Chadda

    Department of Biochemistry & Molecular Biophysics, Washington University in St Louis, St. Louis, United States
    Competing interests
    No competing interests declared.
  2. Nathan Bernhardt

    Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. Elizabeth G Kelley

    Center for Neutron Research, National Institute for Standards and Technology, Gaithersburg, United States
    Competing interests
    No competing interests declared.
  4. Susana C M Teixeira

    Chemical and Biomolecular Engineering, University of Delaware, Newark, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6603-7936
  5. Kacie Griffith

    Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  6. Alejandro Gil-Ley

    Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Tuğba N Öztürk

    Department of Biochemistry & Molecular Biophysics, Washington University in St Louis, St. Louis, United States
    Competing interests
    No competing interests declared.
  8. Lauren E Hughes

    Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  9. Ana Forsythe

    Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  10. Venkatramanan Krishnamani

    Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  11. José D Faraldo-Gómez

    Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    For correspondence
    jfg4wrk@gmail.com
    Competing interests
    José D Faraldo-Gómez, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7224-7676
  12. Janice L Robertson

    Department of Biochemistry & Molecular Biophysics, Washington University in St Louis, St. Louis, United States
    For correspondence
    janice.robertson@wustl.edu
    Competing interests
    Janice L Robertson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5499-9943

Funding

National Institute of General Medical Sciences (R01GM120260)

  • Janice L Robertson

National Institute of General Medical Sciences (R21GM126476)

  • Janice L Robertson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Merritt Maduke, Stanford University School of Medicine, United States

Version history

  1. Received: September 20, 2020
  2. Accepted: April 6, 2021
  3. Accepted Manuscript published: April 7, 2021 (version 1)
  4. Version of Record published: May 12, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Rahul Chadda
  2. Nathan Bernhardt
  3. Elizabeth G Kelley
  4. Susana C M Teixeira
  5. Kacie Griffith
  6. Alejandro Gil-Ley
  7. Tuğba N Öztürk
  8. Lauren E Hughes
  9. Ana Forsythe
  10. Venkatramanan Krishnamani
  11. José D Faraldo-Gómez
  12. Janice L Robertson
(2021)
Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states
eLife 10:e63288.
https://doi.org/10.7554/eLife.63288

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https://doi.org/10.7554/eLife.63288