Wiltzius_et_al-2009-Protein_Science

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1、AtomicstructuresofIAPP(amylin)fusionssuggestamechanismforfibrillationandtheroleofinsulinintheprocessJedJ.W.Wiltzius,StuartA.Sievers,MichaelR.Sawaya,andDavidEisenberg*HowardHughesMedicalInstitute,UCLA-DOEInstituteofGenomicsandProteomics,LosAngeles,California90095-1

2、570Received13February2009;Revised7April2009;Accepted9April2009DOI:10.1002/pro.145Publishedonline29April2009proteinscience.orgAbstract:IsletAmyloidPolypeptide(IAPPoramylin)isapeptidehormoneproducedandstoredintheb-isletcellsofthepancreasalongwithinsulin.IAPPreadilyf

3、ormsamyloidfibrilsinvitro,andthedepositionoffibrillarIAPPhasbeencorrelatedwiththepathologyoftypeIIdiabetes.ThemechanismoftheconversionthatIAPPundergoesfromsolubletofibrillarformshasbeenunclear.BychaperoningIAPPthroughfusiontomaltosebindingprotein,wefindthatIAPPcan

4、adoptaa-helicalstructureatresidues8–18and22–27andthatmoleculesofIAPPdimerize.Mutationalanalysissuggeststhatthisdimerizationisonthepathwaytofibrillation.ThestructuresuggestshowIAPPmayheterodimerizewithinsulin,whichweconfirmedbyproteincrosslinking.Takentogether,thes

5、eexperimentssuggestthehelicaldimerizationofIAPPacceleratesfibrilformationandthatinsulinimpedesfibrillationbyblockingtheIAPPdimerizationinterface.Keywords:IAPP;amylin;amyloid;aggregation;typeIIdiabetesIntroductionthediseaseappearstocorrelatewiththedegreeofpla-10Isl

6、etamyloidpolypeptide(IAPPoramylin)hasbeenquedeposition.IAPPhasbeenshowntobehighly1113implicatedinthepathologyoftypeIIdiabetes,adis-cytotoxictoculturedisletcells.Thistoxicityiseasethataffectsanestimated20millionpeopleinthebelievedtobeconnectedtotheisletcelllossobse

7、rved1inthediseasedstate.SincetheisletcellsalsoproduceUnitedStates.Thediseaseischaracterizedinitiallybyaconditionofinsulinresistanceandprogressesinsulin,itisbelievedthisisthecauseoftheprogres-2siontoinsulindependence.14MouseIAPPdiffersfromtowardsinsulindependence.N

8、earlyalltypeIIdia-beticsexhibitamyloidplaquesinthepancreascom-humaninonlysixof37residuesbutthemousepep-15posedprimarilyofthemature,37-residueformoftided