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Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations
[Image: see text] The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010359/ https://www.ncbi.nlm.nih.gov/pubmed/27459426 http://dx.doi.org/10.1021/jacs.6b05602 |
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author | Lelimousin, Mickaël Limongelli, Vittorio Sansom, Mark S. P. |
author_facet | Lelimousin, Mickaël Limongelli, Vittorio Sansom, Mark S. P. |
author_sort | Lelimousin, Mickaël |
collection | PubMed |
description | [Image: see text] The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process. The lowest energy state of the TM domain is a right-handed dimer structure in which the TM helices interact through the N-terminal small-X(3)-small sequence motif. In addition to this state, which is thought to correspond to the active form of the receptor, we have identified further low-energy states that allow us to integrate with a high level of detail a range of previous experimental observations. These conformations may lead to the active state via two possible activation pathways, which involve pivoting and rotational motions of the helices, respectively. Molecular dynamics also reveals correlation between the conformational changes of the TM domains and of the intracellular juxtamembrane domains, paving the way for a comprehensive understanding of EGFR signaling at the cell membrane. |
format | Online Article Text |
id | pubmed-5010359 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-50103592016-09-06 Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations Lelimousin, Mickaël Limongelli, Vittorio Sansom, Mark S. P. J Am Chem Soc [Image: see text] The epidermal growth factor receptor (EGFR) is a dimeric membrane protein that regulates key aspects of cellular function. Activation of the EGFR is linked to changes in the conformation of the transmembrane (TM) domain, brought about by changes in interactions of the TM helices of the membrane lipid bilayer. Using an advanced computational approach that combines Coarse-Grained molecular dynamics and well-tempered MetaDynamics (CG-MetaD), we characterize the large-scale motions of the TM helices, simulating multiple association and dissociation events between the helices in membrane, thus leading to a free energy landscape of the dimerization process. The lowest energy state of the TM domain is a right-handed dimer structure in which the TM helices interact through the N-terminal small-X(3)-small sequence motif. In addition to this state, which is thought to correspond to the active form of the receptor, we have identified further low-energy states that allow us to integrate with a high level of detail a range of previous experimental observations. These conformations may lead to the active state via two possible activation pathways, which involve pivoting and rotational motions of the helices, respectively. Molecular dynamics also reveals correlation between the conformational changes of the TM domains and of the intracellular juxtamembrane domains, paving the way for a comprehensive understanding of EGFR signaling at the cell membrane. American Chemical Society 2016-07-26 2016-08-24 /pmc/articles/PMC5010359/ /pubmed/27459426 http://dx.doi.org/10.1021/jacs.6b05602 Text en Copyright © 2016 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Lelimousin, Mickaël Limongelli, Vittorio Sansom, Mark S. P. Conformational Changes in the Epidermal Growth Factor Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained MetaDynamics Free Energy Calculations |
title | Conformational
Changes in the Epidermal Growth Factor
Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained
MetaDynamics Free Energy Calculations |
title_full | Conformational
Changes in the Epidermal Growth Factor
Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained
MetaDynamics Free Energy Calculations |
title_fullStr | Conformational
Changes in the Epidermal Growth Factor
Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained
MetaDynamics Free Energy Calculations |
title_full_unstemmed | Conformational
Changes in the Epidermal Growth Factor
Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained
MetaDynamics Free Energy Calculations |
title_short | Conformational
Changes in the Epidermal Growth Factor
Receptor: Role of the Transmembrane Domain Investigated by Coarse-Grained
MetaDynamics Free Energy Calculations |
title_sort | conformational
changes in the epidermal growth factor
receptor: role of the transmembrane domain investigated by coarse-grained
metadynamics free energy calculations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010359/ https://www.ncbi.nlm.nih.gov/pubmed/27459426 http://dx.doi.org/10.1021/jacs.6b05602 |
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