Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region Implications for Dimerization and Activation Mechanisms 英文参考文献.docVIP

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Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region Implications for Dimerization and Activation Mechanisms 英文参考文献.doc

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Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region Implications for Dimerization and Activation Mechanisms 英文参考文献

MutationD816VAlterstheInternalStructureand Dynamicsofc-KITReceptorCytoplasmicRegion: ImplicationsforDimerizationandActivation Mechanisms ElodieLaine*,IsaureChauvotdeBeauche?ne,DavidPerahia,ChristianAuclair,LubaTchertanov* LBPA,CNRS-ENSdeCachan,Cachan,France Abstract The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylationeventsthatareassociatedwithaswitchingoftheproteinconformationbetweeninactiveandactivestates. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutivelyactive,andresistanttotreatmentwiththeanti-cancerdrugImatinib.Toelucidatetheactivatingmolecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normalmodesanalysis(NMA)andbindingsiteprediction.Multiple50-nsMDsimulationsofwild-typeKITanditsmutant D816Vwererecordedusingtheinactiveauto-inhibitedstructureoftheprotein,characteristicoftypeIIIRTKs.Computed freeenergydifferencesenabledustoquantifytheimpactofD816Vonproteinstabilityintheinactivestate.Weevidenceda localstructuralalterationoftheactivationloop(A-loop)uponmutation,andalong-rangestructuralre-organizationofthe juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normalmodeanalysisofseveralMDconformationsledtoaplausiblemolecularrationaletoproposethatJMRisableto depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutantdimerizationwithouttheneedforextra-cellularligandbinding.PocketdetectionatthesurfaceofNMA-displaced conformationsfinallyrevealedthatdetachmentofJMRfromthekinasedomaininthemutantwassufficienttoopenan accesstothecatalyticandsubstratebindingsites. Citation:LaineE,ChauvotdeBeauche?neI,PerahiaD,AuclairC,TchertanovL(2011)MutationD816VAlterstheInternalStructureandDynamicsofc-KITReceptor CytoplasmicRegion:Impli