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Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE

GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic...

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Autores principales: Ke, Meng, Yuan, Yafei, Jiang, Xin, Yan, Nieng, Gong, Haipeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491310/
https://www.ncbi.nlm.nih.gov/pubmed/28617850
http://dx.doi.org/10.1371/journal.pcbi.1005603
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author Ke, Meng
Yuan, Yafei
Jiang, Xin
Yan, Nieng
Gong, Haipeng
author_facet Ke, Meng
Yuan, Yafei
Jiang, Xin
Yan, Nieng
Gong, Haipeng
author_sort Ke, Meng
collection PubMed
description GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic residue (Asp27 in XylE) and a neutral one (Asn29 in GLUT1) is a key element for their mechanistic divergence. In this work, we combined computational and biochemical approaches to investigate the mechanism of proton coupling by XylE and the functional divergence between GLUT1 and XylE. Using molecular dynamics simulations, we evaluated the free energy profiles of the transition between inward- and outward-facing conformations for the apo proteins. Our results revealed the correlation between the protonation state and conformational preference in XylE, which is supported by the crystal structures. In addition, our simulations suggested a thermodynamic difference between XylE and GLUT1 that cannot be explained by the single residue variation at the protonation site. To understand the molecular basis, we applied Bayesian network models to analyze the alteration in the architecture of the hydrogen bond networks during conformational transition. The models and subsequent experimental validation suggest that multiple residue substitutions are required to produce the thermodynamic and functional distinction between XylE and GLUT1. Despite the lack of simulation studies with substrates, these computational and biochemical characterizations provide unprecedented insight into the mechanistic difference between proton symporters and uniporters.
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spelling pubmed-54913102017-07-18 Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE Ke, Meng Yuan, Yafei Jiang, Xin Yan, Nieng Gong, Haipeng PLoS Comput Biol Research Article GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic residue (Asp27 in XylE) and a neutral one (Asn29 in GLUT1) is a key element for their mechanistic divergence. In this work, we combined computational and biochemical approaches to investigate the mechanism of proton coupling by XylE and the functional divergence between GLUT1 and XylE. Using molecular dynamics simulations, we evaluated the free energy profiles of the transition between inward- and outward-facing conformations for the apo proteins. Our results revealed the correlation between the protonation state and conformational preference in XylE, which is supported by the crystal structures. In addition, our simulations suggested a thermodynamic difference between XylE and GLUT1 that cannot be explained by the single residue variation at the protonation site. To understand the molecular basis, we applied Bayesian network models to analyze the alteration in the architecture of the hydrogen bond networks during conformational transition. The models and subsequent experimental validation suggest that multiple residue substitutions are required to produce the thermodynamic and functional distinction between XylE and GLUT1. Despite the lack of simulation studies with substrates, these computational and biochemical characterizations provide unprecedented insight into the mechanistic difference between proton symporters and uniporters. Public Library of Science 2017-06-15 /pmc/articles/PMC5491310/ /pubmed/28617850 http://dx.doi.org/10.1371/journal.pcbi.1005603 Text en © 2017 Ke et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ke, Meng
Yuan, Yafei
Jiang, Xin
Yan, Nieng
Gong, Haipeng
Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title_full Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title_fullStr Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title_full_unstemmed Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title_short Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE
title_sort molecular determinants for the thermodynamic and functional divergence of uniporter glut1 and proton symporter xyle
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491310/
https://www.ncbi.nlm.nih.gov/pubmed/28617850
http://dx.doi.org/10.1371/journal.pcbi.1005603
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