Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding 英文参考文献.docVIP

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Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding 英文参考文献.doc

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Diminished Self-Chaperoning Activity of the ΔF508 Mutant of CFTR Results in Protein Misfolding 英文参考文献

DiminishedSelf-ChaperoningActivityoftheDF508 MutantofCFTRResultsinProteinMisfolding AdrianW.R.Serohijos1.,Tama′sHegedu?s2,3.,JohnR.Riordan2,3,NikolayV.Dokholyan2* 1DepartmentofPhysicsandAstronomy,UniversityofNorthCarolinaChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,2DepartmentofBiochemistryand Biophysics,UniversityofNorthCarolinaChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,3CysticFibrosisResearchCenter,UniversityofNorthCarolina ChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica Abstract The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator(CFTR)fromapicalmembranesofepithelialcellsisresponsibleforcysticfibrosis(CF).Over90%ofCFpatients carryatleastonemutantallelewithdeletionofphenylalanineatposition508locatedintheN-terminalnucleotidebinding domain (NBD1). Biochemical and cell biological studies show that the DF508 mutant exhibits inefficient biosynthetic maturationandsusceptibilitytodegradationprobablyduetomisfoldingofNBD1andtheresultantmisassemblyofother domains.However,littleisknownaboutthedirecteffectofthePhe508deletionontheNBD1folding,whichisessentialfor rationaldesignstrategiesofcysticfibrosistreatment.HereweshowthatthedeletionofPhe508altersthefoldingdynamics andkineticsofNBD1,thuspossiblyaffectingtheassemblyofthecompleteCFTR.Usingmoleculardynamicssimulations,we findthatmeta-stableintermediatestatesappearingonwildtypeandmutantfoldingpathwaysarepopulateddifferently andthattheirkineticaccessibilitiesaredistinct.Thestructuralbasisoftheincreasedmisfoldingpropensityofthe DF508 NBD1mutantistheperturbationofinteractionsinresiduepairsQ493/P574andF575/F578foundinloopS7-H6.Asaproof- of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutationsintheidentifiedcriticalinteractionstoforcetheS7-H6loopintothewildtypeconformation.Tworedesigned NBD1-DF508 variants exhibited significantly higher folding p