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Structure. 2012 Apr 4;20(4):604-17. doi: 10.1016/j.str.2012.02.001. Epub 2012 Apr 3.

Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53.

Author information

1
Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg (IREBS), Boulevard Sébastien Brant, BP 10413, 67412 Illkirch, France. zanier@unistra.fr

Abstract

The viral oncoprotein E6 is an essential factor for cervical cancers induced by "high-risk" mucosal HPV. Among other oncogenic activities, E6 recruits the ubiquitin ligase E6AP to promote the ubiquitination and subsequent proteasomal degradation of p53. E6 is prone to self-association, which long precluded its structural analysis. Here we found that E6 specifically dimerizes through its N-terminal domain and that disruption of the dimer interface strongly increases E6 solubility. This allowed us to raise structural data covering the entire HPV16 E6 protein, including the high-resolution NMR structures of the two zinc-binding domains of E6 and a robust data-driven model structure of the N-terminal domain homodimer. Interestingly, homodimer interface mutations that disrupt E6 self-association also inactivate E6-mediated p53 degradation. These data suggest that E6 needs to self-associate via its N-terminal domain to promote the polyubiquitination of p53 by E6AP.

PMID:
22483108
PMCID:
PMC3325491
DOI:
10.1016/j.str.2012.02.001
[Indexed for MEDLINE]
Free PMC Article

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