Ubiquitin-protein ligase E3A (E6-AP)–Tumor protein p53 (p53) interface (E6-AP–p53 interface)

The E6-AP–p53 interface represents a pivotal protein-protein interaction (PPI) exploited by high-risk Human Papillomaviruses (HPV) to drive oncogenesis (PMID: 27120158). In HPV-infected cells, the viral E6 oncoprotein recruits the host E3 ubiquitin ligase E6-AP (also known as UBE3A, UniProt: Q06520) to form a ternary complex with the tumor suppressor protein p53 (UniProt: P04637). This interaction facilitates the polyubiquitination of p53, leading to its rapid degradation via the 26S proteasome and the subsequent loss of cell cycle control and apoptotic signaling (PMID: 10426991). Because p53 degradation is a hallmark of HPV-induced cancers, such as cervical and head and neck squamous cell carcinomas, this interface is a high-priority therapeutic target. Small molecules and peptidomimetics designed to disrupt this complex aim to stabilize p53, thereby restoring its ability to induce growth arrest or apoptosis in malignant cells (PMID: 24658274). However, drug development is complicated by the need for high selectivity to avoid interfering with the essential neuronal functions of E6-AP, which is linked to Angelman syndrome. Current research focuses on identifying compounds that specifically block the E6-binding pocket or the E6-AP/p53 recruitment site without affecting the ligase's endogenous substrates (PMID: 27657134).

Other names

UBE3A-p53 interfaceE6AP-p53 interactionHPV E6-E6AP-p53 complexE6-mediated p53 degradation complex

Inhibition of E6-mediated p53 ubiquitination and degradation; Restoration of p53-dependent tumor suppression