Linear schematic of an E6 protein

The E6 proteins have been best studied in the oncogenic HPVs where they interact with, and often degrade, host proteins that regulate cell proliferation. High risk E6 proteins interact with E6-AP, a ubiquitin ligase, to promote degradation of p53 and PDZ domain containing proteins involved in cell polarity. E6 also activates telomerase by degrading a transcriptional repressor that regulates telomerase expression. In addition, E6 proteins interfere with p300-mediated acetylation of p53, interact with the focal adhesion protein paxillin and abrogate the interferon response. E6 is approximately 150 amino acids in length and consists of two zinc binding domains flanked by short N-terminal and C-terminal tails. In the oncogenic E6 proteins, the Cterminal region (C) contains a motif that interacts with PDZ domain containing proteins. The E6 protein is encoded by most papillomaviruses. Exceptions are the Xipapillomaviruses, which do not encode E6 and instead have an E5-like protein in this position and the HPVs from gamma species-6. Reptilian papillomavirus E6 proteins contain only one zinc binding domain. The high risk Alphapapillomaviruses also express a series of spliced messages (E6*I-IV) that encode short E6* polypeptides which consist of half of the first zinc binding domain. E6* proteins can bind full-length E6 and E6AP.

Prediction of the E6*I transcript

The E6* viral transcript is produced by splicing within the E6 ORF. Within so-called high-risk Alphapapillomaviruses the splice donor site is highly conserved. The spliced transcript encodes a protein that contains the first CXXC zinc-binding motif of E6 and then a few amino acids of variable non-conserved sequence following the acceptor site. To date, the E6* spliced mRNA has not been described in other viral species or genera (reviewed in Vande Pol and Klingelhutz, 2013). Currently, PaVE has annotated experimentally validated E6* proteins (Mesplede et al., 2012). Efforts to use sequence homology to aid in prediction of additional E6* proteins are underway.