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1、ConformationsofIsletAmyloidPolypeptideMonomersinaMembraneEnvironment:ImplicationsforFibrilFormationMojieDuan,JueFan,ShuanghongHuo*GustafH.CarlsonSchoolofChemistryandBiochemistry,ClarkUniversity,Worcester,Massachusetts,UnitedStatesofAmericaAbstractThe
2、amyloidfibrilsformedbyisletamyloidpolypeptide(IAPP)areassociatedwithtypeIIdiabetes.OneoftheproposedmechanismsofthetoxicityofIAPPisthatitcausesmembranedamage.ThefatalmutationofS20GhumanIAPPwasreportedtoleadtoearlyonsetoftypeIIdiabetesandhightendencyof
3、amyloidformationinvitro.CharacterizingthestructuralfeaturesoftheS20Gmutantinitsmonomericstateisexperimentallydifficultbecauseofitsunusuallyfastaggregationrate.Computationalworkcomplementsexperimentalstudies.Weperformedaseriesofmoleculardynamicssimula
4、tionsofthemonomericstateofhumanvariantsinthemembrane.Oursimulationsarevalidatedbyextensivecomparisonswithexperimentaldata.WefindthatahelicaldisruptionatHis18iscommontobothhumanvariants.AnL-shapedmotifofS20Gmutantisobservedinoneoftheconformationalfami
5、lies.ThismotifthatbendsatHis18resemblestheoveralltopologyofIAPPfibrils.Theconformationalpreorganizationintothefibril-liketopologyprovidesapossibleexplanationforthefastaggregationrateofS20GIAPP.Citation:DuanM,FanJ,HuoS(2012)ConformationsofIsletAmyloid
6、PolypeptideMonomersinaMembraneEnvironment:ImplicationsforFibrilFormation.PLoSONE7(11):e47150.doi:10.1371/journal.pone.0047150Editor:IliaV.Baskakov,UniversityofMaryland,UnitedStatesofAmericaReceivedJuly24,2012;AcceptedSeptember12,2012;PublishedNovembe
7、r2,2012Copyright:ß2012Duanetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Funding:Thiswork
8、isfundedbyNationalInstitutesofHealth(1R01-GM088326).Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist.*E-mail:shuo@clarku.e
