Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons

Abstract The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Laurie Verzeaux, Nicolas Belloy, Jessica Thevenard-Devy, Jérôme Devy, Géraldine Ferracci, Laurent Martiny, Stéphane Dedieu, Manuel Dauchez, Hervé Emonard, Nicolas Etique, Emmanuelle Devarenne-Charpentier
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/16e3c09a1b4d4103a912523a3d0bd5d9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:16e3c09a1b4d4103a912523a3d0bd5d9
record_format	dspace
spelling	oai:doaj.org-article:16e3c09a1b4d4103a912523a3d0bd5d92021-12-02T12:32:55ZIntrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons10.1038/s41598-017-05039-z2045-2322https://doaj.org/article/16e3c09a1b4d4103a912523a3d0bd5d92017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05039-zhttps://doaj.org/toc/2045-2322Abstract The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis mediated by the low-density lipoprotein receptor-related protein-1 (LRP-1). To gain insight into the interaction between TIMP-1 and LRP-1, we considered conformational changes that occur when a ligand binds to its receptor. TIMP-1 conformational changes have been studied using biomolecular simulations, and our results provide evidence for a hinge region that is critical for the protein movement between the N- and C-terminal TIMP-1 domains. In silico mutants have been proposed on residues F12 and K47, which are located in the hinge region. Biological analyses of these mutants show that F12A or K47A mutation does not alter MMP inhibitory activity but impairs the effect of TIMP-1 on neurite outgrowth. Interestingly, these mutants bind to LRP-1 but are not endocytosed. We conclude that the intrinsic dynamics of TIMP-1 are not involved in its binding to LRP-1 but rather in the initiation of endocytosis and associated biological effects.Laurie VerzeauxNicolas BelloyJessica Thevenard-DevyJérôme DevyGéraldine FerracciLaurent MartinyStéphane DedieuManuel DauchezHervé EmonardNicolas EtiqueEmmanuelle Devarenne-CharpentierNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laurie Verzeaux Nicolas Belloy Jessica Thevenard-Devy Jérôme Devy Géraldine Ferracci Laurent Martiny Stéphane Dedieu Manuel Dauchez Hervé Emonard Nicolas Etique Emmanuelle Devarenne-Charpentier Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
description	Abstract The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis mediated by the low-density lipoprotein receptor-related protein-1 (LRP-1). To gain insight into the interaction between TIMP-1 and LRP-1, we considered conformational changes that occur when a ligand binds to its receptor. TIMP-1 conformational changes have been studied using biomolecular simulations, and our results provide evidence for a hinge region that is critical for the protein movement between the N- and C-terminal TIMP-1 domains. In silico mutants have been proposed on residues F12 and K47, which are located in the hinge region. Biological analyses of these mutants show that F12A or K47A mutation does not alter MMP inhibitory activity but impairs the effect of TIMP-1 on neurite outgrowth. Interestingly, these mutants bind to LRP-1 but are not endocytosed. We conclude that the intrinsic dynamics of TIMP-1 are not involved in its binding to LRP-1 but rather in the initiation of endocytosis and associated biological effects.
format	article
author	Laurie Verzeaux Nicolas Belloy Jessica Thevenard-Devy Jérôme Devy Géraldine Ferracci Laurent Martiny Stéphane Dedieu Manuel Dauchez Hervé Emonard Nicolas Etique Emmanuelle Devarenne-Charpentier
author_facet	Laurie Verzeaux Nicolas Belloy Jessica Thevenard-Devy Jérôme Devy Géraldine Ferracci Laurent Martiny Stéphane Dedieu Manuel Dauchez Hervé Emonard Nicolas Etique Emmanuelle Devarenne-Charpentier
author_sort	Laurie Verzeaux
title	Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
title_short	Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
title_full	Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
title_fullStr	Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
title_full_unstemmed	Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons
title_sort	intrinsic dynamics study identifies two amino acids of timp-1 critical for its lrp-1-mediated endocytosis in neurons
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/16e3c09a1b4d4103a912523a3d0bd5d9
work_keys_str_mv	AT laurieverzeaux intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT nicolasbelloy intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT jessicathevenarddevy intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT jeromedevy intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT geraldineferracci intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT laurentmartiny intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT stephanededieu intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT manueldauchez intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT herveemonard intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT nicolasetique intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons AT emmanuelledevarennecharpentier intrinsicdynamicsstudyidentifiestwoaminoacidsoftimp1criticalforitslrp1mediatedendocytosisinneurons
_version_	1718393902706196480

Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons

Ejemplares similares