Abstract
Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target proteins. Here, we first summarize the diverse activities of these small multifunctional oncoproteins. Next, we review the available structural data and the new insights they provide about the evolution of E6 and E7, their multiple interactions and their functional variability across human papillomavirus (HPV) species.
Highlights
Papillomaviruses (PVs) constitute a large family of small oncogenic DNA viruses that infect mucosal or cutaneous epithelia [1,2]
Is likely an acquiredStructures property that emerged for the mammalian and E7 proteins were identified as major PV oncoproteins in the mid-80s [81,82,83,84,85], papillomaviruses immediately promoting the first attempts to produce these proteins in recombinant form [86,87,88,89]
The structures of zinc-binding domains of several E6 and E7 proteins have been solved by Nuclear Magnetic Resonance (NMR) and crystallography, revealing two zinc-binding folds probably derived from a common ancestor
Summary
Papillomaviruses (PVs) constitute a large family of small oncogenic DNA viruses that infect mucosal or cutaneous epithelia [1,2]. The two main viral HPV oncogenes required to establish and maintain the tumorigenic phenotype encode two early expressed oncoproteins, called E6 and E7 Both E6 and E7 are very small proteins (in most mammalian PVs about 150 and 100 amino acids, respectively). Turning off the expression of E6 oncoprotein in HPV-positive cancer-derived cells by means of RNA interference induces growth arrest followed by either apoptosis or senescence [1,19,20,21]. Blocking E6 molecular activities by means of E6-binding recombinant proteins [22], peptides [23,24,25], or antibodies [26,27] has been shown to drive growth arrest and/or death of HPV-positive tumor cells These data indicate that well-designed small molecule ligands of E6 will represent promising avenues for therapy of HPV-positive cancers. A prerequisite for the ab initio design of such small molecule inhibitors, and for the rationale improvement of current low-affinity E6 inhibitors [28,29,30], is to obtain high-resolution information on the three-dimensional structure of E6 proteins alone or in complex with their cellular targets
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