Molecular Basis of Filamin A-FilGAP Interaction and Its Impairment in Congenital Disorders Associated with Filamin A Mutations 英文参考文献.docVIP

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Molecular Basis of Filamin A-FilGAP Interaction and Its Impairment in Congenital Disorders Associated with Filamin A Mutations 英文参考文献.doc

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Molecular Basis of Filamin A-FilGAP Interaction and Its Impairment in Congenital Disorders Associated with Filamin A Mutations 英文参考文献

MolecularBasisofFilaminA-FilGAPInteractionandIts ImpairmentinCongenitalDisordersAssociatedwith FilaminAMutations FumihikoNakamura1*,OutiHeikkinen2,OlliT.Pentika¨inen3,TeresiaM.Osborn1,KarenE.Kasza4, DavidA.Weitz4,OlgaKupiainen2,PerttuPermi5,IlkkaKilpela¨inen2,JariYla¨nne3,JohnH.Hartwig1, ThomasP.Stossel1 1TranslationalMedicineDivision,DepartmentofMedicine,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica, 2LaboratoryofOrganicChemistry,DepartmentofChemistry,UniversityofHelsinki,Helsinki,Finland,3DepartmentofBiologicalandEnvironmentalScience,Universityof Jyva¨skyla¨, Jyva¨skyla¨, Finland,4DepartmentofPhysicsSEAS,HarvardUniversity,Cambridge,Massachusetts,UnitedStatesofAmerica,5PrograminStructuralBiology andBiophysics,InstituteofBiotechnology,UniversityofHelsinki,Helsinki,Finland Abstract Background: Mutations in filamin A (FLNa), an essential cytoskeletal protein with multiple binding partners, cause developmentalanomaliesinhumans. Methodology/PrincipalFindings:Wedeterminedthestructureofthe23rdIgrepeatofFLNa(IgFLNa23)thatinteractswith FilGAP,aRac-specificGTPase-activatingproteinandregulatorofcellpolarityandmovement,andtheeffectofthethree disease-relatedmutationsonthisinteraction.AcombinationofNMRstructuralanalysisandinsilicomodelingrevealedthe structural interface details between the C and D b-strands of the IgFLNa23 and the C-terminal 32 residues of FilGAP. Mutagenesisofthepredictedkeyinterfaceresiduesconfirmedthebindingconstraintsbetweenthetwoproteins.Specific loss-of-functionFLNaconstructsweregeneratedandusedtoanalyzetheimportanceoftheFLNa-FilGAPinteractioninvivo. PointmutagenesisrevealedthatdisruptionoftheFLNa-FilGAPinterfaceperturbscellspreading.FilGAPdoesnotbindFLNa homologs FLNb or FLNc establishing the importance of this interaction to the human FLNa mutations. Tight complex formationrequiresdimerizationofbothpartnersandthecorrectalignmentofthebindingsurfaces,whichispromotedbya flexible hinge domain between repeats 23 a