Journal
STRUCTURE
Volume 20, Issue 4, Pages 604-617Publisher
CELL PRESS
DOI: 10.1016/j.str.2012.02.001
Keywords
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Funding
- Centre National do la Recherche Scientifique (CNRS)
- Association pour la Recherche sur le Cancer [ARC-2007 3171]
- National Institute of Health [NIH R01CA134737]
- Ligue Nationale Contre le Cancer
- Agence Nationale de la Recherche [ANR-06-BLAN-0404, ANR-MIME-2007 EPI-HPV-3D]
- Fondation pour la Recherche Medicate (FRM)
- Arbor Vita Corporation (Sunnyvale, CA)
- Agence Nationale de la Recherche (ANR) [ANR-06-BLAN-0404] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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