ABSTRACT
Human papillomavirus type 16 (HPV-16) E6 (16E6) binds the E3 ubiquitin ligase E6AP and p53, thereby targeting degradation of p53 (M. Scheffner, B. A. Werness, J. M. Huibregtse, A. J. Levine, and P. M. Howley, Cell 63:1129-1136, 1990). Here we show that minimal 16E6-binding LXXLL peptides reshape 16E6 to confer p53 interaction and stabilize 16E6 in vivo but that degradation of p53 by 16E6 requires E6AP expression. These experiments establish a general mechanism for how papillomavirus E6 binding to LXXLL peptides reshapes E6 to then act as an adapter molecule.
Subject(s)
Human papillomavirus 16/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nerve Tissue Proteins/metabolism , Oncogene Proteins, Viral/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Cycle Proteins , Cell Line , Intracellular Signaling Peptides and Proteins/chemistry , Mice , Nerve Tissue Proteins/chemistry , Oncogene Proteins, Viral/chemistry , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Repressor Proteins/chemistry , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae/virology , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases/biosynthesis , Ubiquitin-Protein Ligases/chemistryABSTRACT
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.