Large-scale state-dependent membrane remodeling by a transporter protein
- National Heart, Lung and Blood Institute, National Institutes of Health, United States
- Children's National Medical Center, United States
- 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.
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Simulation files for "Large-scale state-dependent membrane remodeling by a transporter protein"Zenodo, doi:10.5281/zenodo.3558957.
Article and author information
Author details
José D Faraldo-Gómez
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.
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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Large-scale state-dependent membrane remodeling by a transporter protein
eLife 8:e50576.
https://doi.org/10.7554/eLife.50576
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