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Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme

Lipid bilayer provides a two-dimensional hydrophobic solvent milieu for membrane proteins in cells. Although the native bilayer is widely recognized as an optimal environment for folding and function of membrane proteins, the underlying physical basis remains elusive. Here, employing the intramembra...

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Autores principales: Muhammednazaar, Shaima, Yao, Jiaqi, Guo, Ruiqiong, Rhee, May S., Kim, Kelly H., Kang, Seung-gu, Hong, Heedeok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312574/
https://www.ncbi.nlm.nih.gov/pubmed/37398072
http://dx.doi.org/10.1101/2023.05.30.542905
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author Muhammednazaar, Shaima
Yao, Jiaqi
Guo, Ruiqiong
Rhee, May S.
Kim, Kelly H.
Kang, Seung-gu
Hong, Heedeok
author_facet Muhammednazaar, Shaima
Yao, Jiaqi
Guo, Ruiqiong
Rhee, May S.
Kim, Kelly H.
Kang, Seung-gu
Hong, Heedeok
author_sort Muhammednazaar, Shaima
collection PubMed
description Lipid bilayer provides a two-dimensional hydrophobic solvent milieu for membrane proteins in cells. Although the native bilayer is widely recognized as an optimal environment for folding and function of membrane proteins, the underlying physical basis remains elusive. Here, employing the intramembrane protease GlpG of Escherichia coli as a model, we elucidate how the bilayer stabilizes a membrane protein and engages the protein’s residue interaction network compared to the nonnative hydrophobic medium, micelles. We find that the bilayer enhances GlpG stability by promoting residue burial in the protein interior compared to micelles. Strikingly, while the cooperative residue interactions cluster into multiple distinct regions in micelles, the whole packed regions of the protein act as a single cooperative unit in the bilayer. Molecular dynamics (MD) simulation indicates that lipids less efficiently solvate GlpG than detergents. Thus, the bilayerinduced enhancement of stability and cooperativity likely stems from the dominant intraprotein interactions outcompeting the weak lipid solvation. Our findings reveal a foundational mechanism in the folding, function, and quality control of membrane proteins. The enhanced cooperativity benefits function facilitating propagation of local structural perturbation across the membrane. However, the same phenomenon can render the proteins’ conformational integrity vulnerable to missense mutations causing conformational diseases(1,2).
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spelling pubmed-103125742023-07-01 Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme Muhammednazaar, Shaima Yao, Jiaqi Guo, Ruiqiong Rhee, May S. Kim, Kelly H. Kang, Seung-gu Hong, Heedeok bioRxiv Article Lipid bilayer provides a two-dimensional hydrophobic solvent milieu for membrane proteins in cells. Although the native bilayer is widely recognized as an optimal environment for folding and function of membrane proteins, the underlying physical basis remains elusive. Here, employing the intramembrane protease GlpG of Escherichia coli as a model, we elucidate how the bilayer stabilizes a membrane protein and engages the protein’s residue interaction network compared to the nonnative hydrophobic medium, micelles. We find that the bilayer enhances GlpG stability by promoting residue burial in the protein interior compared to micelles. Strikingly, while the cooperative residue interactions cluster into multiple distinct regions in micelles, the whole packed regions of the protein act as a single cooperative unit in the bilayer. Molecular dynamics (MD) simulation indicates that lipids less efficiently solvate GlpG than detergents. Thus, the bilayerinduced enhancement of stability and cooperativity likely stems from the dominant intraprotein interactions outcompeting the weak lipid solvation. Our findings reveal a foundational mechanism in the folding, function, and quality control of membrane proteins. The enhanced cooperativity benefits function facilitating propagation of local structural perturbation across the membrane. However, the same phenomenon can render the proteins’ conformational integrity vulnerable to missense mutations causing conformational diseases(1,2). Cold Spring Harbor Laboratory 2023-05-31 /pmc/articles/PMC10312574/ /pubmed/37398072 http://dx.doi.org/10.1101/2023.05.30.542905 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Muhammednazaar, Shaima
Yao, Jiaqi
Guo, Ruiqiong
Rhee, May S.
Kim, Kelly H.
Kang, Seung-gu
Hong, Heedeok
Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title_full Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title_fullStr Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title_full_unstemmed Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title_short Lipid Bilayer Strengthens the Cooperative Network of a Membrane-Integral Enzyme
title_sort lipid bilayer strengthens the cooperative network of a membrane-integral enzyme
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312574/
https://www.ncbi.nlm.nih.gov/pubmed/37398072
http://dx.doi.org/10.1101/2023.05.30.542905
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