SEDLIN Forms Homodimers Characterisation of SEDLIN Mutations and Their Interactions with Transcription Factors MBP1, PITX1 and SF1 英文参考文献.docVIP

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SEDLIN Forms Homodimers Characterisation of SEDLIN Mutations and Their Interactions with Transcription Factors MBP1, PITX1 and SF1 英文参考文献.doc

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SEDLIN Forms Homodimers Characterisation of SEDLIN Mutations and Their Interactions with Transcription Factors MBP1, PITX1 and SF1 英文参考文献

SEDLINFormsHomodimers:CharacterisationofSEDLIN MutationsandTheirInteractionswithTranscription FactorsMBP1,PITX1andSF1 JeshmiJeyabalan1,M.AndrewNesbit1,JurisGalvanovskis2,RichardCallaghan3,PatrikRorsman2, RajeshV.Thakker1* 1AcademicEndocrineUnit,NuffieldDepartmentofClinicalMedicine,OxfordCentreforDiabetes,EndocrinologyandMetabolism,UniversityofOxford,ChurchillHospital, Oxford, United Kingdom, 2Diabetes Research Laboratories, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom, 3Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford,UnitedKingdom Abstract Background:SEDLIN,a140aminoacidsubunitoftheTransportProteinParticle(TRAPP)complex,isubiquitouslyexpressed and interactswith the transcription factors c-myc promoter-binding protein 1 (MBP1),pituitary homeobox 1 (PITX1) and steroidogenicfactor1(SF1).SEDLINmutationscauseX-linkedspondyloepiphysealdysplasiatarda(SEDT). Methodology/PrincipalFindings:Weinvestigatedtheeffectsof4missense(Asp47Tyr,Ser73Leu,Phe83SerandVal130Asp) andthemostC-terminalnonsense(Gln131Stop)SEDT-associatedmutationsoninteractionswithMBP1,PITX1andSF1by expressioninCOS7cells.Wild-typeSEDLINwaspresentinthecytoplasmandnucleusandinteractedwithMBP1,PITX1and SF1;theSEDLINmutationsdidnotalterthesesubcellularlocalizationsortheinteractions.However,SEDLINwasfoundto homodimerize,andtheformationofdimersbetweenwild-typeandmutantSEDLINwouldmaskalossintheseinteractions. AmammalianSEDLINnullcell-lineisnotavailable,andtheinteractionsbetweenSEDLINandthetranscriptionfactorswere thereforeinvestigatedinyeast,whichdoesnotendogenouslyexpressSEDLIN.ThisrevealedthatalltheSEDTmutations, exceptAsp47Tyr,leadtoalossofinteractionwithMBP1,PITX1andSF1.Three-dimensionalmodellingstudiesofSEDLIN revealedthatAsp47residesonthesurfacewhereasalltheothermutantresiduesliewithinthehydrophobiccoreofthe protein,andhencearelikelytoaf