A Cu²⁺ complex induces the aggregation of human papillomavirus oncoprotein E6 and stabilizes p53

Abstract

Papillomavirus oncoprotein E6 is a critical factor in the modulation of cervical cancer in humans. At the molecular level, formation of the E6-E6AP-p53 ternary complex, which directs p53's degradation, is the key instigator of cancer transforming properties. Herein, a Cu anthracenyl-terpyridine complex is described which specifically induces the aggregation of E6 in vitro and in cultured cells. For a hijacking mechanism, both E6 and E6AP are required for p53 ubiquitination and degradation. The Cu complex interacts with E6 at the E6AP and p53 binding sites. We show that E6 function is suppressed by aggregation, rendering it incapable of hijacking p53 and thus increasing its cellular level. Therapeutic treatments of cervical cancer are currently unavailable to infected individuals. We anticipate that this Cu complex might open up a new therapeutic avenue for the design and development of new chemical entities for the diagnosis and treatment of HPV-induced cancers.

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

“…Notably, the coordination of Zn 2+ by the HPV16 E7 protein produces a compact environment leading to its self-assembly into spherical oligomers similar to those found in amyloids, whereas Zn 2+ depletion results in loss of its aggregation [ 219 , 220 , 221 ]. HPV E6 protein also forms Zn 2+ -dependent soluble agglomerates, whereas the metal chelating agent EDTA stabilizes its monomeric form and destabilizes existing agglomerates [ 89 ], and where Cu 2+ complexes also cause E6 aggregation, inhibiting its function [ 222 ]. Recent work has demonstrated that the keratinocyte-derived body’s epidermal barrier is formed by the filaggrin protein [ 223 ], a protein that phase-separates and that has been found to bind Cu 2+ and be regulated by Zn 2+ [ 224 ].…”

Human papillomavirus infection, cervical cancer and the less explored role of trace elements

“…Molecularly, E6-E6AP-p53 complex leads to the destruction of p53, a vital mediator of pro-cancer transforming protein. The binding sites of E6AP and p53 facilitates the interaction of anthracenyl-terpyridine Cu 2+ complex with E6 [ 196 ]. The complex stimulated in vitro E6 aggregation in cultured cells.…”