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On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation
Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential T...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893634/ https://www.ncbi.nlm.nih.gov/pubmed/29636500 http://dx.doi.org/10.1038/s41598-018-23778-5 |
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author | Pagani, Giulia Gohlke, Holger |
author_facet | Pagani, Giulia Gohlke, Holger |
author_sort | Pagani, Giulia |
collection | PubMed |
description | Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin α(IIb)β(3), α(v)β(3), and α(5)β(1) that α(IIb)β(3) TMD is most stably associated; this difference is related to interaction differences across the TMDs. The order of TMD association stability is paralleled by the basal activity of these integrins, which suggests that TMD differences can have a decisive effect on integrin conformational free energies. We also identified a specific order of clasp disintegration upon TMD dissociation, which suggests that the closed state of integrins may comprise several microstates. Our results provide unprecedented insights into a possibly contributing role of TMD towards subunit-specific sensitivity of integrin activation. |
format | Online Article Text |
id | pubmed-5893634 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58936342018-04-12 On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation Pagani, Giulia Gohlke, Holger Sci Rep Article Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin α(IIb)β(3), α(v)β(3), and α(5)β(1) that α(IIb)β(3) TMD is most stably associated; this difference is related to interaction differences across the TMDs. The order of TMD association stability is paralleled by the basal activity of these integrins, which suggests that TMD differences can have a decisive effect on integrin conformational free energies. We also identified a specific order of clasp disintegration upon TMD dissociation, which suggests that the closed state of integrins may comprise several microstates. Our results provide unprecedented insights into a possibly contributing role of TMD towards subunit-specific sensitivity of integrin activation. Nature Publishing Group UK 2018-04-10 /pmc/articles/PMC5893634/ /pubmed/29636500 http://dx.doi.org/10.1038/s41598-018-23778-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Pagani, Giulia Gohlke, Holger On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title | On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title_full | On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title_fullStr | On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title_full_unstemmed | On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title_short | On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
title_sort | on the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893634/ https://www.ncbi.nlm.nih.gov/pubmed/29636500 http://dx.doi.org/10.1038/s41598-018-23778-5 |
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