Allosteric Modulation of PS1γ-Secretase Conformation Correlates with Amyloid β4240 Ratio 英文参考文献.docVIP

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Allosteric Modulation of PS1γ-Secretase Conformation Correlates with Amyloid β4240 Ratio 英文参考文献.doc

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Allosteric Modulation of PS1γ-Secretase Conformation Correlates with Amyloid β4240 Ratio 英文参考文献

AllostericModulationofPS1/c-SecretaseConformation CorrelateswithAmyloidb42/40 Ratio KengoUemura1,ChristinaM.Lill1,XuejingLi1,JessicaA.Peters1,AlexanderIvanov1,ZhanyunFan1 ,Bart DeStrooper2,BrianJ.Bacskai1,BradleyT.Hyman1,OksanaBerezovska1* 1AlzheimerResearchUnit,MassGeneralInstituteforNeurodegenerativeDiseases,MassachusettsGeneralHospital,Charlestown,Massachusetts,UnitedStatesofAmerica, 2LaboratoryofNeuronalCellBiologyandGeneTransfer,KatholiekeUniversiteitLeuven,Leuven,Belgium Abstract Background:Presenilin1(PS1)isthecatalyticsubunitofc-secretase,theenzymeresponsiblefortheAbC-terminalcleavage site,whichresultsintheproductionofAbpeptidesofvariouslengths.ProductionoflongerformsoftheAbpeptideoccur in patients with autosomal dominant Alzheimer disease (AD) due to mutations in presenilin. Many modulators of c- secretase function have been described. We hypothesize that these modulators act by a common mechanism by allostericallymodifyingthestructureofpresenilin. Methodology/PrincipalFindings:TotestthishypothesiswegeneratedageneticallyencodedGFP-PS1-RFP(G-PS1-R)FRET probethatallowsmonitoringoftheconformationofthePS1moleculeinitsnativeenvironmentinlivecells.Weshowthat G-PS1-Rcanbeincorporatedintothec-secretasecomplex,reconstitutingitsactivityinPS1/2deficientcells.UsingFo¨rster resonanceenergytransfer(FRET)-basedapproachesweshowthatvariouspharmacologicalandgeneticmanipulationsthat targeteitherc-secretasecomponents(PS1,Pen2,Aph1)orc-secretasesubstrate(amyloidprecursorprotein,APP)andare knowntochangeAb42productionareassociatedwithaconsistentconformationalchangeinPS1. Conclusions/Significance: These results strongly support the hypothesis that allosteric changes in PS1 conformation underliechangesintheAb42/40ratio.Directmeasurementofphysiologicalandpathologicalchangesintheconformationof PS1/c-secretase may provide insight into molecular mechanism of Ab42 generation, which could be exploited therapeutically. Citation: Uemura K, Lill CM, Li X, Peters JA, Ivanov A, et al. (2