HPV E6, E6AP and cervical cancer

Abstract

Every year, approximately 470,000 new cases of cervical cancer are diagnosed and approximately 230,000 women worldwide die of the disease, with the majority (approximately 80%) of these cases and deaths occurring in developing countries. Human papillomaviruses (HPVs) are the etiological agents in nearly all cases (99.7%) of cervical cancer, and the HPV E6 protein is one of two viral oncoproteins that is expressed in virtually all HPV-positive cancers. E6 hijacks a cellular ubiquitin ligase, E6AP, resulting in the ubiquitylation and degradation of the p53 tumor suppressor, as well as several other cellular proteins. While the recent introduction of prophylactic vaccines against specific HPV types offers great promise for prevention of cervical cancer, there remains a need for therapeutics. Biochemical characterization of E6 and E6AP has suggested approaches for interfering with the activities of these proteins that could be useful for this purpose. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Figure 1

Structural and functional domains of E6AP and E6. The schematic of E6AP (also known as UBE3A) indicates the location of the E6 binding site (E6 BS) and the catalytic HECT domain. The two zinc binding domains and the C-terminal PDZ binding epitope of HPV16 E6 are indicated. Some of the targets that are inactivated by the E6/E6AP complex are indicated.

Figure 2

The X-ray crystal structure of the complex of the E6AP HECT domain with UbcH7 (PDB 1DF5). The HECT N lobe (blue), linker (red) and C lobe (green) are indicated. UbcH7 (magenta) was co-crystallized with the HECT domain, while ubiquitin (black) is modeled into the structure shown based on a Ubc1-ubiquitin model [72] (PDB 1FXT). The dashed line represents the 41 Å line-of-site between the active-site cysteines of UbcH7 and E6AP. Adapted from [38].