Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2 英文参考文献.docVIP

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Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2 英文参考文献.doc

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Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2 英文参考文献

EffectsofS1CleavageontheStructure,SurfaceExport, andSignalingActivityofHumanNotch1andNotch2 WendyR.Gordon1,DidemVardar-Ulu2,SarahL’Heureux1,ToddAshworth1,MichaelJ.Malecki1 ,Cheryll Sanchez-Irizarry1¤,DebbieG.McArthur1,GavinHisten1,JenniferL.Mitchell1,JonC.Aster1,StephenC. Blacklow1* 1DepartmentofPathology,BrighamandWomen’sHospitalandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,2DepartmentofChemistry, WellesleyCollege,Wellesley,Massachusetts,UnitedStatesofAmerica Abstract Background:Notchreceptorsarenormallycleavedduringmaturationbyafurin-likeproteaseatanextracellularsitetermed S1,creatingaheterodimerofnon-covalentlyassociatedsubunits.TheS1sitelieswithinakeynegativeregulatoryregion (NRR)ofthereceptor,whichcontainsthreehighlyconservedLin12/Notchrepeatsandaheterodimerizationdomain(HD) thatinteracttopreventprematuresignalingintheabsenceofligands.BecausetheroleofS1cleavageinNotchsignaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in humanleukemia. PrincipalFindings:TheX-raystructureoftheNotch1NRRafterfurincleavageshowslittlechangewhencomparedwiththat ofanengineeredNotch1NRRlackingtheS1-cleavageloop.Likewise,NMRstudiesoftheNotch2HDdomainshowthatthe loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand- mediatedreceptoractivation,whereasS1-resistantNotch2receptorsarefullycompetentforcellsurfacedeliveryandfor activationbyligands.VariabledependenceonS1cleavagealsoextendstoT-ALL-associatedNRRmutations,ascommon class 1 mutations display variable decrements in ligand-independent