E6*, the 50 amino acid product of the most abundant spliced transcript of the e6 oncoprotein in high-risk human papillomavirus, is a promiscuous folder and binder.

High-risk human papillomavirus E6 participates in tumorigenic progression, mainly by its ability to promote p53 degradation. HPV transcripts show a complex splicing pattern, where E6* is the most abundant transcript in high-risk HPV types, comprising the first 50 amino acids of E6. No structural or biochemical information of this polypeptide, which contains half of the first zinc binding motif of E6, is available, due to the difficulty to acquire a compact monomeric fold in such a small polypeptide. We show that HPV16-E6* can fold into either α-helix or ß-sheet large oligomers at pH 7.5 and 5.0, respectively, in the absence of zinc. The ß-sheet oligomers are highly stable and unaffected by the presence of zinc, while the α-helix oligomers tend to rapidly form aggregates, prevented by the presence of the metal. Two E6* molecules bind per atom of zinc, suggesting a tetrahedral, high-affinity arrangement (K(D) < 10(-12) M), which results in a zinc-mediated E6* dimer with significant secondary structure. Endogenous E6 oligomers were previously found in the cytosol of high-risk HPV transformed cell lines, and we propose that the oligomerization determinant resides within E6*. E6* effects were reported to counteract those of E6 in cells, and the ratio between these two species modulates p53 degradation and other apoptosis-dependent signaling cascades. A residue of an evolved splicing event related to regulation of oncogene expression in HPV or a splicing event resulting from the selection of a small deleterious viral polypeptide, the abundant existence of E6* with a "chameleon" nature correlates with target plasticity, and its fate is linked to a balance between protein levels, zinc availability, redox potential, and oligomerization. In addition, the results presented here have strong implications for zinc binding sites in nascent polypeptides. This evolved promiscuous folder speaks of effect rather than function of a viral product that, when highly increased, can directly or indirectly affect various cellular processes leading to cell deregulation and tumorigenesis.