INTRINSIC DISORDER IN THE HUMAN PAPILLOMAVIRUS E7 PROTEIN

CHEMES LB; SÁNCHEZ IE; ALONSO, LG; DE PRAT GAY G

Flexible viruses: structural disorder within viral proteins

John Wiley and sons

Año: 2012;

E7 is a prototypic viral oncoprotein, not only responsible for the cellular transformation behind one of the most widespread cancers in women, but with counterparts in other wellknown small DNA tumour viruses. This highly acidic and weak dimer displays a modular domain arrangement, anomalous hydrodynamic properties, and is classified as an intrinsically disordered protein. The N-terminal domain of HPV E7 (E7N) is responsible for its intrinsically disordered nature, and although it is neither compact nor cooperatively folded, it is a bona fide domain, evolved to maintain a dynamic and extended, yet stable fold within the cell. E7 shows an enormous plasticity for target protein recognition. The structural and molecular basis for this recognition plasticity derives from several features of E7, such as the presence of several short protein-protein recognition motifs located in the intrinsically disordered and extended N-terminal domain, and the potential to accrue different backbone conformations, which are largely dependent on the chemical environment. Additional recognition sites located in the C-terminal domain and multiple oligomerization states, observed both in vitro and within cells, add to E7 recognition plasticity. These features allow E7 to interact in a network-like manner. We describe a few interaction mechanisms that have been biochemically dissected, including a possible enzymatic activity of E7 as a chaperone holdase. Finally, we discuss the role of intrinsic disorder in the evolution of E7, and possible similarities with oncoproteins from related DNA tumour viruses. The flexible structure of the N-terminal intrinsically disordered domain allows for a high density of functional motifs and for the fast incorporation of new functions through only a few point mutations.