Fibrillization of Human Tau Is Accelerated by Exposure to Lead via Interaction with His-330 and His-362 英文参考文献.docVIP

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Fibrillization of Human Tau Is Accelerated by Exposure to Lead via Interaction with His-330 and His-362 英文参考文献.doc

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Fibrillization of Human Tau Is Accelerated by Exposure to Lead via Interaction with His-330 and His-362 英文参考文献

FibrillizationofHumanTauIsAcceleratedbyExposureto LeadviaInteractionwithHis-330andHis-362 Hai-LiZhu,Sheng-RongMeng,Jun-BaoFan,JieChen,YiLiang* StateKeyLaboratoryofVirology,CollegeofLifeSciences,WuhanUniversity,Wuhan,China Abstract Background:Neurofibrillarytangles,mainlyconsistedofbundlesoffilamentsformedbythemicrotubule-associatedprotein Tau, are a hallmark of Alzheimer disease. Lead is a potent neurotoxin for human being especially for the developing 2+ children,andPb athighconcentrationsisfoundinthebrainsofpatientswithAlzheimerdisease.However,ithasnotbeen reportedsofarwhetherPb playsaroleinthepathologyofAlzheimerdiseasethroughinteractionwithhumanTauprotein 2+ 2+ andtherebymediatesTaufilamentformation.Inthisstudy,wehaveinvestigatedtheeffectofPb onfibrilformationof recombinanthumanTaufragmentTau244–372 anditsmutantsatphysiologicalpH. Methodology/Principal Findings:AsrevealedbythioflavinTand8-anilino-1-naphthalenesulfonicacidfluorescence,the 2+ additionof5–40mMPb significantlyacceleratestheexposureofhydrophobicregionandfilamentformationofwild-type Tau244–372 ontheinvestigatedtimescale.AsevidencedbycirculardichroismandFouriertransforminfraredspectroscopy, 2+ fibrils formed by wild-type Tau244–372 in the presence of 5–40mM Pb contain more b-sheet structure than the same 2+ amountoffibrilsformedbytheproteinintheabsenceofPb .However,unlikewild-typeTau244–372,thepresenceof5– 2+ 40mMPb hasnoobviouseffectsonfibrillizationkineticsofsinglemutantsH330AandH362AanddoublemutantH330A/ H362A,andfibrilsformedbysuchmutantsintheabsenceandinthepresenceofPb containsimilaramountsofb-sheet 2+ structure.TheresultsfromisothermaltitrationcalorimetryshowthatonePb2+bindstooneTaumonomerviainteraction withHis-330andHis-362,withsub-micromolaraffinity. Conclusions/Significance:WedemonstrateforthefirsttimethatthefibrillizationofhumanTauproteinisacceleratedby exposure to lead via interaction with His-330 and His-362. Our results suggest the possible involvement o