Solution Structure of the LIM-Homeodomain Transcription Factor Complex Lhx3Ldb1 and the Effects of a Pituitary Mutation on Key Lhx3 Interactions 英文参考文献.docVIP

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Solution Structure of the LIM-Homeodomain Transcription Factor Complex Lhx3Ldb1 and the Effects of a Pituitary Mutation on Key Lhx3 Interactions 英文参考文献.doc

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Solution Structure of the LIM-Homeodomain Transcription Factor Complex Lhx3Ldb1 and the Effects of a Pituitary Mutation on Key Lhx3 Interactions 英文参考文献

SolutionStructureoftheLIM-Homeodomain TranscriptionFactorComplexLhx3/Ldb1andtheEffects ofaPituitaryMutationonKeyLhx3Interactions MugdhaBhati.¤a,ChristopherLee.,MorganS.Gadd.,CyM.Jeffries¤b,AnnKwan,AndrewE.Whitten¤c, JillTrewhella,JoelP.Mackay,JacquelineM.Matthews* SchoolofMolecularBioscience,UniversityofSydney,Sydney,NewSouthWales,Australia Abstract Lhx3 is a LIM-homeodomain (LIM-HD) transcription factor that regulates neural cell subtype specification and pituitary development in vertebrates, and mutations in this protein cause combined pituitary hormone deficiency syndrome (CPHDS).TherecentlypublishedstructuresofLhx3incomplexwitheachoftwokeyproteinpartners,Isl1andLdb1,provide an opportunity to understand the effect of mutations and posttranslational modifications on key protein-protein interactions.Here,weusesmall-angleX-rayscatteringofanLdb1-Lhx3complextoconfirmthatinsolutiontheproteinis wellrepresentedby ourpreviouslydeterminedNMRstructureasanensemble ofconformerseachcomprisingtwowell- definedhalves(eachmadeupofLIMdomainfromLhx3andthecorrespondingbindingmotifinLdb1)withsomeflexibility betweenthetwohalves.NMRanalysisofanLhx3mutantthatcausesCPHDS,Lhx3(Y114C),showsthatthemutationdoes notalterthezinc-ligationpropertiesofLhx3,butappearstocauseastructuralrearrangementofthehydrophobiccoreof theLIM2domainofLhx3thatdestabilisesthedomainand/orreducestheaffinityofLhx3forbothLdb1andIsl1.Thusthe mutationwouldaffecttheformationofLhx3-containingtranscriptionfactorcomplexes,particularlyinthepituitarygland wherethesecomplexesarerequiredfortheproductionofmultiplepituitarycelltypesandhormones. Citation:BhatiM,LeeC,GaddMS,JeffriesCM,KwanA,etal.(2012)SolutionStructureoftheLIM-HomeodomainTranscriptionFactorComplexLhx3/Ldb1and theEffectsofaPituitaryMutationonKeyLhx3Interactions.PLoSONE7(7):e40719.doi:10.1371/journal.pone.0040719 Editor:RenwickDobson,UniversityofCanterbury,NewZealand ReceivedMay15,2012;AcceptedJune12,2012;PublishedJuly25,2012 Copyright: ? 2012 Bhati et al. This i