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Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116059/ https://www.ncbi.nlm.nih.gov/pubmed/33825681 http://dx.doi.org/10.7554/eLife.63288 |
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author | Chadda, Rahul Bernhardt, Nathan Kelley, Elizabeth G Teixeira, Susana CM Griffith, Kacie Gil-Ley, Alejandro Öztürk, Tuğba N Hughes, Lauren E Forsythe, Ana Krishnamani, Venkatramanan Faraldo-Gómez, José D Robertson, Janice L |
author_facet | Chadda, Rahul Bernhardt, Nathan Kelley, Elizabeth G Teixeira, Susana CM Griffith, Kacie Gil-Ley, Alejandro Öztürk, Tuğba N Hughes, Lauren E Forsythe, Ana Krishnamani, Venkatramanan Faraldo-Gómez, José D Robertson, Janice L |
author_sort | Chadda, Rahul |
collection | PubMed |
description | 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 toward 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. |
format | Online Article Text |
id | pubmed-8116059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-81160592021-05-14 Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states Chadda, Rahul Bernhardt, Nathan Kelley, Elizabeth G Teixeira, Susana CM Griffith, Kacie Gil-Ley, Alejandro Öztürk, Tuğba N Hughes, Lauren E Forsythe, Ana Krishnamani, Venkatramanan Faraldo-Gómez, José D Robertson, Janice L eLife Structural Biology and Molecular Biophysics 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 toward 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. eLife Sciences Publications, Ltd 2021-04-07 /pmc/articles/PMC8116059/ /pubmed/33825681 http://dx.doi.org/10.7554/eLife.63288 Text en https://creativecommons.org/publicdomain/zero/1.0/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 (https://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Structural Biology and Molecular Biophysics Chadda, Rahul Bernhardt, Nathan Kelley, Elizabeth G Teixeira, Susana CM Griffith, Kacie Gil-Ley, Alejandro Öztürk, Tuğba N Hughes, Lauren E Forsythe, Ana Krishnamani, Venkatramanan Faraldo-Gómez, José D Robertson, Janice L Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title | Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title_full | Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title_fullStr | Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title_full_unstemmed | Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title_short | Membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
title_sort | membrane transporter dimerization driven by differential lipid solvation energetics of dissociated and associated states |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116059/ https://www.ncbi.nlm.nih.gov/pubmed/33825681 http://dx.doi.org/10.7554/eLife.63288 |
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