In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Abstract Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent mol...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Matthieu Goguet, Tarun Jairaj Narwani, Rachel Petermann, Vincent Jallu, Alexandre G. de Brevern
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/78993e28dd484f5d8a86ac350d7f3950
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:78993e28dd484f5d8a86ac350d7f3950
record_format	dspace
spelling	oai:doaj.org-article:78993e28dd484f5d8a86ac350d7f39502021-12-02T15:06:09ZIn silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect10.1038/s41598-017-08408-w2045-2322https://doaj.org/article/78993e28dd484f5d8a86ac350d7f39502017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08408-whttps://doaj.org/toc/2045-2322Abstract Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired αIIbβ3 expression. This method is aimed at studying all αIIbβ3 sub-domains and impact of missense mutations at local and global structural level.Matthieu GoguetTarun Jairaj NarwaniRachel PetermannVincent JalluAlexandre G. de BrevernNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthieu Goguet Tarun Jairaj Narwani Rachel Petermann Vincent Jallu Alexandre G. de Brevern In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
description	Abstract Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired αIIbβ3 expression. This method is aimed at studying all αIIbβ3 sub-domains and impact of missense mutations at local and global structural level.
format	article
author	Matthieu Goguet Tarun Jairaj Narwani Rachel Petermann Vincent Jallu Alexandre G. de Brevern
author_facet	Matthieu Goguet Tarun Jairaj Narwani Rachel Petermann Vincent Jallu Alexandre G. de Brevern
author_sort	Matthieu Goguet
title	In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
title_short	In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
title_full	In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
title_fullStr	In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
title_full_unstemmed	In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect
title_sort	in silico analysis of glanzmann variants of calf-1 domain of αiibβ3 integrin revealed dynamic allosteric effect
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/78993e28dd484f5d8a86ac350d7f3950
work_keys_str_mv	AT matthieugoguet insilicoanalysisofglanzmannvariantsofcalf1domainofaiibb3integrinrevealeddynamicallostericeffect AT tarunjairajnarwani insilicoanalysisofglanzmannvariantsofcalf1domainofaiibb3integrinrevealeddynamicallostericeffect AT rachelpetermann insilicoanalysisofglanzmannvariantsofcalf1domainofaiibb3integrinrevealeddynamicallostericeffect AT vincentjallu insilicoanalysisofglanzmannvariantsofcalf1domainofaiibb3integrinrevealeddynamicallostericeffect AT alexandregdebrevern insilicoanalysisofglanzmannvariantsofcalf1domainofaiibb3integrinrevealeddynamicallostericeffect
_version_	1718388590564605952

In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Ejemplares similares