Abstract
E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Bovine papillomavirus 1
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Crystallography, X-Ray
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Human papillomavirus 16
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Humans
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Molecular Dynamics Simulation
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Molecular Sequence Data
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Oncogene Proteins, Viral / chemistry*
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism*
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Paxillin / chemistry*
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Paxillin / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Point Mutation
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Protein Interaction Domains and Motifs*
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Protein Structure, Secondary
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Repressor Proteins / chemistry*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / chemistry*
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Ubiquitin-Protein Ligases / metabolism
Substances
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E6 protein, Human papillomavirus type 16
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Oncogene Proteins, Viral
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Paxillin
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Peptide Fragments
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Repressor Proteins
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protein E6, Bovine papillomavirus
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UBE3A protein, human
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Ubiquitin-Protein Ligases