Large-scale state-dependent membrane remodeling by a transporter protein

  1. Wenchang Zhou
  2. Giacomo Fiorin
  3. Claudio Anselmi
  4. Hossein Ali Karimi-Varzaneh
  5. Horacio Poblete
  6. Lucy Forrest  Is a corresponding author
  7. José D Faraldo-Gómez  Is a corresponding author
  1. National Heart, Lung and Blood Institute, National Institutes of Health, United States
  2. Children's National Medical Center, United States
  3. National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Abstract

That channels and transporters can influence the membrane morphology is increasingly recognized. Less appreciated is that the extent and free-energy cost of these deformations likely varies among different functional states of a protein, and thus, that they might contribute significantly to defining its mechanism. We consider the trimeric Na+-aspartate symporter GltPh, a homolog of an important class of neurotransmitter transporters, whose mechanism entails one of the most drastic structural changes known. Molecular simulations indicate that when the protomers become inward-facing, they cause deep, long-ranged, and yet mutually-independent membrane deformations. Using a novel simulation methodology, we estimate that the free-energy cost of this membrane perturbation is in the order of 6-7 kcal/mol per protomer. Compensating free-energy contributions within the protein or its environment must thus stabilize this inward-facing conformation for the transporter to function. We discuss these striking results in the context of existing experimental observations for this and other transporters.

Data availability

Input and output files for 1 (out of 3) replica of each simulation system/condition in our study have been uploaded to Zenodo, a public repository free of charge, and is available at the DOI 10.5281/zenodo.3558957.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Wenchang Zhou

    Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0397-1032
  2. Giacomo Fiorin

    Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  3. Claudio Anselmi

    Research Center for Genetic Medicine, Children's National Medical Center, Bethesda, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3017-5085
  4. Hossein Ali Karimi-Varzaneh

    Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  5. Horacio Poblete

    Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  6. Lucy Forrest

    Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    For correspondence
    lucy.forrest@nih.gov
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1855-7985
  7. José D Faraldo-Gómez

    Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States
    For correspondence
    jose.faraldo@nih.gov
    Competing interests
    José D Faraldo-Gómez, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7224-7676

Funding

National Heart, Lung, and Blood Institute

  • Wenchang Zhou
  • Giacomo Fiorin
  • Claudio Anselmi
  • José D Faraldo-Gómez

National Institute of Neurological Disorders and Stroke

  • Hossein Ali Karimi-Varzaneh
  • Horacio Poblete
  • Lucy Forrest

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

Reviewing Editor

  1. Nir Ben-Tal, Tel Aviv University, Israel

Publication history

  1. Received: July 26, 2019
  2. Accepted: December 17, 2019
  3. Accepted Manuscript published: December 19, 2019 (version 1)
  4. Version of Record published: January 13, 2020 (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. Wenchang Zhou
  2. Giacomo Fiorin
  3. Claudio Anselmi
  4. Hossein Ali Karimi-Varzaneh
  5. Horacio Poblete
  6. Lucy Forrest
  7. José D Faraldo-Gómez
(2019)
Large-scale state-dependent membrane remodeling by a transporter protein
eLife 8:e50576.
https://doi.org/10.7554/eLife.50576

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