Asymmetric Switching in a Homodimeric ABC Transporter A Simulation Study 英文参考文献.docVIP

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Asymmetric Switching in a Homodimeric ABC Transporter A Simulation Study 英文参考文献.doc

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Asymmetric Switching in a Homodimeric ABC Transporter A Simulation Study 英文参考文献

AsymmetricSwitchinginaHomodimericABC Transporter:ASimulationStudy JussiAittoniemi1,2,HeidideWet2,FrancesM.Ashcroft2,MarkS.P.Sansom1* 1Department of Biochemistry, University of Oxford, Oxford, United Kingdom, 2Department of Physiology, Anatomy Genetics, University of Oxford, Oxford, United Kingdom Abstract ABCtransportersarealargefamilyofmembraneproteinsinvolvedinavarietyofcellularprocesses,includingmultidrugand tumorresistanceandionchannelregulation.AdvancesinthestructuralandfunctionalunderstandingofABCtransporters haverevealedthathydrolysisatthetwocanonicalnucleotide-bindingsites(NBSs)isco-operativeandnon-simultaneous.A conservedcorearchitectureofbacterialandeukaryoticABCexportershasbeenestablished,asexemplifiedbythecrystal structureofthehomodimericmultidrugexporterSav1866.Currently,itisunclearhowsequentialATPhydrolysisarisesina symmetric homodimeric transporter, since it implies at least transient asymmetry at the NBSs. We show by molecular dynamicssimulationthattheinitiallysymmetricstructureofSav1866readilyundergoesasymmetrictransitionsatitsNBSsin apre-hydrolyticnucleotideconfiguration.MgATP-bindingresiduesandanetworkofchargedresiduesatthedimerinterface areshowntoformasequenceofputativemolecularswitchesthatallowATPhydrolysisonlyatoneNBS.Weextendour findingstoeukaryoticABCexporterswhichoftenconsistoftwonon-identicalhalf-transporters,frequentlywithdegeneracy substitutions at one of their two NBSs. Interestingly, many residues involved in asymmetric conformational switching in Sav1866aresubstitutedindegenerateeukaryoticNBS.Thisfindingstrengthensrecentsuggestionsthattheinterplayofa consensusandadegenerateNBSineukaroyticABCproteinspre-determinesthesequenceofhydrolysisatthetwoNBSs. Citation:AittoniemiJ,deWetH,AshcroftFM,SansomMSP(2010)AsymmetricSwitchinginaHomodimericABCTransporter:ASimulationStudy.PLoSComput Biol6(4):e1000762.doi:10.1371/journal.pcbi.1000762 Editor:MichaelM.Gottesman,NationalCancerInstitute,UnitedStatesofAmerica ReceivedOctober20,2009;AcceptedMarch