Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer 英文参考文献.docVIP
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Aβ Peptide Fibrillar Architectures Controlled by Conformational Constraints of the Monomer 英文参考文献
AbPeptideFibrillarArchitecturesControlledby
ConformationalConstraintsoftheMonomer
KristofferBra¨nnstro¨m1,AndersOhman¨ 2*,AndersOlofsson1*
1DepartmentofMedicalBiochemistryandBiophysics,Umea? University,Umea?, Sweden,2DepartmentofChemistry,Umea? University,Umea?, Sweden
Abstract
Anomalousself-assemblyoftheAbpeptideintofibrillaramyloiddepositsisstronglycorrelatedwiththedevelopmentof
Alzheimer’s disease. Ab fibril extension follows a template guided ‘‘dock and lock’’ mechanism where polymerisation is
catalysedbythefibrillarends.Usingsurfaceplasmonresonance(SPR)andquenchedhydrogen-deuteriumexchangeNMR
(H/D-exchangeNMR),wehaveanalysedthefibrillarstructureandpolymerisationpropertiesofboththehighlyaggregation
prone Ab1–40 Glu22Gly (Ab40Arc) and wild type Ab1–40 (Ab40WT). The solvent protection patterns from H/D exchange
experimentssuggestverysimilarstructuresofthefibrillarforms.However,throughcross-seedingexperimentsmonitored
bySPR,wefoundthatthemonomericformofAb40WTissignificantlyimpairedtoacquirethefibrillararchitectureofAb40Arc
.
A detailed characterisation demonstrated that Ab40WT has a restricted ability to dock and isomerise with high binding
affinity onto Ab40Arc fibrils. These results have general implications for the process of fibril assembly, where the rate of
polymerisation,andconsequentlythearchitectureoftheformedfibrils,isrestrictedbyconformationalconstraintsofthe
monomers.Interestingly,wealsofoundthatthekineticrateoffibrilformationratherthanthethermodynamicallylowest
energystatedeterminestheoverallfibrillarstructure.
Citation:Bra¨nnstro¨mK,O¨hmanA,OlofssonA(2011)AbPeptideFibrillarArchitecturesControlledbyConformationalConstraintsoftheMonomer.PLoSONE6(9):
e25157.doi:10.1371/journal.pone.0025157
Editor:EdatharaAbraham,UniversityofArkansasforMedicalSciences,UnitedStatesofAmerica
ReceivedJune9,2011;AcceptedAugust26,2011;PublishedSeptember29,2011
Copyright:?2011Bra¨nnstro¨metal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommon
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