Proteasomal Degradation of p53 by Human Papillomavirus E6 Oncoprotein Relies on the Structural Integrity of p53 Core Domain 英文参考文献.docVIP

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Proteasomal Degradation of p53 by Human Papillomavirus E6 Oncoprotein Relies on the Structural Integrity of p53 Core Domain 英文参考文献.doc

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Proteasomal Degradation of p53 by Human Papillomavirus E6 Oncoprotein Relies on the Structural Integrity of p53 Core Domain 英文参考文献

ProteasomalDegradationofp53byHuman PapillomavirusE6OncoproteinReliesontheStructural Integrityofp53CoreDomain XavierBernard1,PhilipRobinson2,YvesNomine′1,MurielleMasson1,SebastianCharbonnier1 ,Juan RamonRamirez-Ramos1,FrancoisDeryckere1,GillesTrave′1*,GeorgesOrfanoudakis1* 1Oncoprote′ines, UMR 7242 CNRS, Ecole Supe′rieure de Biotechnologie de Strasbourg, Universite′ de Strasbourg, Illkirch, France, 2Pharmaco-Epide′miologie, CHU de Bordeaux,INSERMCIC0005,Universite′ deBordeaux,Bordeaux,France Abstract The E6 oncoprotein produced by high-risk mucosal HPV stimulates ubiquitinylation and proteasome-dependent degradation of the tumour suppressor p53 via formation of a trimeric complex comprising E6, p53, and E6-AP. p53 is also degraded by its main cellular regulator MDM2. The main binding site of p53 to MDM2 is situated in the natively unfoldedN-terminalregionofp53.Bycontrast,theregionsofp53implicatedinthedegradationbyviralE6arenotfully identifiedtodate.Herewegeneratedaseriesofmutations(Y103G,Y107G,T155A,T155V,T155D,L264A,L265A)targeting thecentralfoldedcoredomainofp53withinaregionoppositetoitsDNA-bindingsite.Weanalysedbyinvitroandinvivo assaystheimpactofthesemutationsonp53degradationmediatedbyviralE6oncoprotein.Whereasallmutantsremained susceptible to MDM2-mediated degradation, several of them (Y103G, Y107G, T155D, L265A) became resistant to E6- mediated degradation, confirming previous works that pointed to the core domain as an essential region for the degradationofp53.Inparallel,wesystematicallycheckedtheimpactofthemutationsonthetransactivationactivityofp53 as well as on the conformation of p53, analysed by Nuclear Magnetic Resonance (NMR), circular dichroism (CD), and antibody probing. These measurements suggested that the conformational integrity of the core domain is an essential parameter for the degradation of p53 by E6, while it is not essential for the degradation of p53 by MDM2. Thus, the intracellularstabilityofaproteinmayormaynotrelyonitsbiophysicalstab