Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium 英文参考文献.docVIP

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Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium 英文参考文献.doc

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Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium 英文参考文献

SmoothenedAdoptsMultipleActiveandInactive ConformationsCapableofTraffickingtothePrimary Cilium ChristopherW.Wilson,Miao-HsuehChen,Pao-TienChuang* CardiovascularResearchInstitute,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica Abstract ActivationofHedgehog(Hh)signalingrequiresthetransmembraneproteinSmoothened(Smo),amemberoftheG-protein coupled receptor superfamily. In mammals, Smo translocates to the primary cilium upon binding of Hh ligands to their receptor, Patched (Ptch1), but it is unclear if ciliary trafficking of Smo is sufficient for pathway activation. Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of Smo, force ciliary translocation of Smo. Treatment with SANT-1, an unrelated Smo antagonist, abrogates cyclopamine- and jervine-mediated Smo translocation. Further,activationofproteinkinaseA,eitherdirectlyorthroughactivationofGas,causesSmototranslocatetoaproximal regionoftheprimarycilium.WeproposethatSmoadoptsmultipleinactiveandactiveconformations,whichinfluenceits localizationandtraffickingontheprimarycilium. Citation: Wilson CW, Chen M-H, Chuang P-T (2009) Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium.PLoSONE4(4):e5182.doi:10.1371/journal.pone.0005182 Editor:RafaelLinden,UniversidadeFederaldoRiodeJaneiro(UFRJ),InstitutodeBiof?′sicadaUFRJ,Brazil ReceivedDecember25,2008;AcceptedMarch15,2009;PublishedApril13,2009 Copyright: ? 2009 Wilson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding:NationalInstitutesofHealth(NIH)andAmericanLungAssociation(ALA).Thefundershadnoroleinstudydesign,datacollectionandanalysis,decision topublish,orpreparationofthemanuscript. CompetingInterests:Theauthorshavedeclaredthatnocompetinginterestsexist. *E-mail:pao-tien.chuan