Human Papillomaviruses (HPV) are small DNA viruses infecting epithelia. More than 200 HPV types have been identified to date. They differ by their tropism (cutaneous/mucosal) and by their oncogenic risk. While the so-called “low-risk” HPVs only cause benign proliferations (warts, condylomas), the high-risk HPVs are at the origin of various cancers: cervix, head and neck, skin, anus… Cervix cancer is essentially caused by oncogenic HPVs, in particular HPV16 and 18, which account for 61 % and 11 % of the cases, respectively (Serrano et al., 2015). In addition, an increasing number of head and neck cancers (oropharynx, oral cavity and larynx) are associated with HPV infection. Of these HPV-positive cancers, 71% are attributed to HPV16 (Castellsagué et al., 2016).
The virus encodes two oncoproteins named E6 and E7, which trigger viral replication by stimulating cellular proliferation. E6 disrupts the function of many cellular proteins by protein-motif interactions. On the one hand, some E6 is equipped with a C-terminal PDZ-binding motif. On the other hand, the two zinc-binding domains of E6 form a hydrophobic pocket which binds to peptide motif of consensus “LxxLL”. A wide variety of cellular proteins harbor such motifs, for instance the E3 ubiquitin ligase E6AP. E6 from HPV16 binds an LxxLL motif located within E6AP (Huibregtse et al. 1993). Once this heterodimer is formed, it recruits the tumor suppressor p53 by its core domain. This complex induces p53 ubiquitinylation, which leads p53 to its proteasomal degradation.
Each E6 protein, produced by a given HPV type, targets a certain set of host proteins, and these interaction preferences contribute to the variability of pathological effects caused by the virus. We explored the interaction preferences of E6 proteins from distinct HPV types for a peptide library entailing putative or published LxxLL target peptides.
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-Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. D Martinez-Zapien et al. Nature, 2016
-Structural Basis for Hijacking of Cellular LxxLL Motifs by Papillomavirus E6 Oncoproteins. K Zanier et al. Science, 2013