Structural and functional analysis of E6 oncoprotein: insights in the molecular pathways of human papillomavirus-mediated pathogenesis.
Oncoprotein E6 is essential for oncogenesis induced by human papillomaviruses (HPVs). The solution structure of HPV16-E6 C-terminal domain reveals a zinc binding fold. A model of full-length E6 is proposed and analyzed in the context of HPV evolution. E6 appears as a chameleon protein combining a conserved structural scaffold with highly variable surfaces participating in generic or specialized HPV functions. We investigated surface residues involved in two specialized activities of high-risk genital HPV E6: p53 tumor suppressor degradation and nucleic acid binding. Screening of E6 surface mutants identified an in vivo p53 degradation-defective mutant that fails to recruit p53 to ubiquitin ligase E6AP and restores high p53 levels in cervical carcinoma cells by competing with endogeneous E6. We also mapped the nucleic acid binding surface of E6, the positive potential of which correlates with genital oncogenicity. E6 structure-function analysis provides new clues for understanding and counteracting the complex pathways of HPV-mediated pathogenesis.
Nominé
Yves
Y
Equipe Oncoprotéine, UMR CNRS 7100, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant, BP 10413, 67412 Illkirch Cedex, France.
Masson
Murielle
M
Charbonnier
Sebastian
S
Zanier
Katia
K
Ristriani
Tutik
T
Deryckère
François
F
Sibler
Annie-Paule
AP
Desplancq
Dominique
D
Atkinson
Robert Andrew
RA
Weiss
Etienne
E
Orfanoudakis
Georges
G
Kieffer
Bruno
B
Travé
Gilles
G
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D027383:Papillomaviridae / Q000737:chemistry* / Q000472:pathogenicity* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
C466080:E6 protein, human papillomavirus type 1; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D004247:DNA; D015032:Zinc