Solution structure of the partially folded high-risk human papilloma virus 45 oncoprotein E7

Abstract

The oncoprotein E7 of human papilloma viruses (HPV) is involved in the pathogenesis and maintenance of human cervical cancers. The most prevalent HPV types found in cervix carcinomas are HPV16, 18 and 45. The structure of the E7 dimer from HPV45 (PDB 2F8B) was determined by nuclear magnetic resonance spectroscopy. Each monomer comprises an unfolded N-terminus and a well-structured C-terminal domain with a b1b2a1b3a2 topology representing a unique zinc-binding fold found only for E7. Dimerization occurs through the a1/a1 0 helices and intermolecular b-sheet formation but excludes the zinc-binding sites. E7 is reported to interact with a number of cellular proteins (e.g. pRb, p21 CIP1 ). Binding of a peptide derived from the C-terminus of p21CIP1 to the Cterminal domain of E7 was characterized by monitoring chemical shift perturbations of the amide groups of E7. This provides direct evidence that a shallow groove situated between a1 and b1 of the E7 C-terminal domain is interacting with the C-terminus of p21 CIP1. Intriguingly, this binding site overlaps with the low-affinity binding site on E7 for the C-domain of pRb.

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

“…The CR1 and CR2 regions of E7 are intrinsically disordered (91,92), whereas CR3 is a zinc binding domain that mediates formation of a homodimer (93,94). The disordered CR1 and CR2 regions of E7 from high risk HPV16 bind with high affinity to the TAZ2 domain of CBP (95).…”

The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections

“…For instance, such a substitution prevents E6 nuclear localization and abolishes its transforming activity (97). The binding of zinc to the CXXC motifs changes the E7 conformation (98) and thus enables dimer formation, even though Zn 2ϩ itself does not seem to participate directly in the interaction between the monomers (135,149). In terms of biological significance, these zinc-binding motifs of the E7 protein are crucial for cell immortalization and malignant transformation (29,125,135) as well as for the stable maintenance of the episomal HPV genome (124).…”

Human Papilloma Virus Immunogen Creation on the Base of Chimeric Recombinant Protein L2e7

“…Всего в одной молекуле L2E7 20 остатков цистеи-на, которые потенциально могут образовывать дисульфидные связи -по 2 остатка цистеина на каждый фрагмент L2 и по 7 остатков в каждой копии Е7. В естественных условиях E7 не обра-зует дисульфидные связи [30], так как, помимо того, что белок находится в цитоплазме клетки (где преобладают восстанавливающие условия), остатки цистеина в правильно свернутой моле-куле пространственно разобщены друг от дру-га. По одной дисульфидной связи в естествен-ных условиях должно образовываться в каждом фрагменте N-конца L2 [7].…”