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Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity

Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N...

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Autores principales: Chauvot de Beauchêne, Isaure, Allain, Ariane, Panel, Nicolas, Laine, Elodie, Trouvé, Alain, Dubreuil, Patrice, Tchertanov, Luba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117417/
https://www.ncbi.nlm.nih.gov/pubmed/25079768
http://dx.doi.org/10.1371/journal.pcbi.1003749
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author Chauvot de Beauchêne, Isaure
Allain, Ariane
Panel, Nicolas
Laine, Elodie
Trouvé, Alain
Dubreuil, Patrice
Tchertanov, Luba
author_facet Chauvot de Beauchêne, Isaure
Allain, Ariane
Panel, Nicolas
Laine, Elodie
Trouvé, Alain
Dubreuil, Patrice
Tchertanov, Luba
author_sort Chauvot de Beauchêne, Isaure
collection PubMed
description Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D) localized in crucial regulatory segments, the juxtamembrane region (JMR) and the activation (A-) loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts.
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spelling pubmed-41174172014-08-04 Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity Chauvot de Beauchêne, Isaure Allain, Ariane Panel, Nicolas Laine, Elodie Trouvé, Alain Dubreuil, Patrice Tchertanov, Luba PLoS Comput Biol Research Article Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D) localized in crucial regulatory segments, the juxtamembrane region (JMR) and the activation (A-) loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts. Public Library of Science 2014-07-31 /pmc/articles/PMC4117417/ /pubmed/25079768 http://dx.doi.org/10.1371/journal.pcbi.1003749 Text en © 2014 Chauvot de Beauchêne 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chauvot de Beauchêne, Isaure
Allain, Ariane
Panel, Nicolas
Laine, Elodie
Trouvé, Alain
Dubreuil, Patrice
Tchertanov, Luba
Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title_full Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title_fullStr Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title_full_unstemmed Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title_short Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
title_sort hotspot mutations in kit receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117417/
https://www.ncbi.nlm.nih.gov/pubmed/25079768
http://dx.doi.org/10.1371/journal.pcbi.1003749
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