Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion 英文参考文献.docVIP

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Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion 英文参考文献.doc

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Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion 英文参考文献

MethionineSulfoxidesonPrionProteinHelix-3Switch onthea-FoldDestabilizationRequiredforConversion GiorgioColombo1*,MassimilianoMeli1,GiuliaMorra1,RuthGabizon2,Mar?′aGasset3* 1Isto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Milano, Italy, 2Department of Neurology, The Agnes Ginges Center for Human Neurogenetics,HadassahUniversityHospital,Jerusalem,Israel,3InstoQu?′mica-F?′sicaRocasolano,ConsejoSuperiordeInvestigacionesCient?′ficas,Madrid,Spain Abstract Background:Theconversionofthecellularprionprotein(PrPC)intotheinfectiousform(PrPSc)isthekeyeventinprion inducedneurodegenerations. Thisprocessis believedtoinvolveamulti-stepconformational transitionfroman a-helical (PrPC)formtoab-sheet-rich(PrPSc)state.Inadditiontotheconformationaldifference,PrPScexhibitsascovalentsignature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studiedtheimpactofmethionineoxidationonthedynamicsandenergeticsoftheHuPrP(125–229)a-fold. Methodology/PrincipalFindings:Usingmoleculardynamicssimulation,essentialdynamics,correlatedmotionsandsignal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stabilityofthenativestateincreasingtheflexibilityofregionsprecedingthesiteofthemodificationandperturbingthe network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essentialintheproductivepathwayofthepathogenicconversion.Thesechangesarealsoobservedwhenthesulfoxidation isplacedatM206andatboth,M206andM213. Conclusions/Significance: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggeringtheinitiala-folddestabilizationrequiredfortheproductivepathogenicconversion. Citation:ColomboG,MeliM,MorraG,GabizonR,GassetM(2009)MethionineSulfoxidesonPrionProteinHelix-3Switchonthea-FoldDestabilizationRequired forConversion.PLoSONE4(1):e4296.doi:10.137