Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53
Copyright policy )Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53
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.
- École Normale Supérieure France
- Institute of Genetics and Molecular and Cellular Biology France
- European Bioinformatics Institute United Kingdom
- European Molecular Biology Laboratory Germany
Models, Molecular, Proteasome Endopeptidase Complex, Binding Sites, Ubiquitin, Ubiquitin-Protein Ligases, Molecular Sequence Data, Ubiquitination, Oncogene Proteins, Viral, Recombinant Proteins, Protein Structure, Tertiary, Repressor Proteins, Structural Biology, Mutation, Escherichia coli, Humans, Amino Acid Sequence, Protein Multimerization, Tumor Suppressor Protein p53, Molecular Biology, Nuclear Magnetic Resonance, Biomolecular, Protein Binding
Models, Molecular, Proteasome Endopeptidase Complex, Binding Sites, Ubiquitin, Ubiquitin-Protein Ligases, Molecular Sequence Data, Ubiquitination, Oncogene Proteins, Viral, Recombinant Proteins, Protein Structure, Tertiary, Repressor Proteins, Structural Biology, Mutation, Escherichia coli, Humans, Amino Acid Sequence, Protein Multimerization, Tumor Suppressor Protein p53, Molecular Biology, Nuclear Magnetic Resonance, Biomolecular, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).107 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!