Targeting and degradation of p53 by E6 of human papillomavirus type 16 is preferential for the 1620+ p53 conformation.
E6-mediated degradation of p53 is believed to play a role in the transformation of cells by high-risk types of human papillomavirus. In order to explore the structural requirements for targeting of p53 we have compared E6-mediated degradation of variant p53 forms expressed in vitro. Complete degradation was observed in samples containing monomers, dimers and higher molecular weight structures of wild-type p53, indicating that E6 targets all quaternary forms of wild-type p53. Wild-type human and murine p53s reactive with PAb 1620 (which recognizes a conformation-dependent epitope) were degraded when incubated with E6. Mutant p53 proteins were variably resistant to E6-mediated degradation, and this correlated with PAb 1620 reactivity. Thus, mutants hp53Val-154, hp53Val-266 and hp53Pro-273 (1620 degrees) were completely resistant to degradation, whereas hp53Ile-247 and hp53Trp-248 (1620+) were degraded. Mutants hp53Leu-273 and mp53Val-135, which are temperature sensitive for conformation, were completely degraded in the 1620+ form but degradation resistant in the 1620 degrees form. Although the PAb 1620+ conformation appeared important for recognition of p53 by E6, the epitope itself is unlikely to be the actual recognition target since the PAb 1620 monoclonal antibody failed to protect against E6-mediated degradation.
Medcalf
E A
EA
Department of Pathology, University of Cambridge, UK.
Milner
J
J
D000939:Epitopes / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D013329:Structure-Activity Relationship; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C068651:E6 protein, Human papillomavirus type 16; D000939:Epitopes; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53