Structural analysis of human papillomavirus E6 interactions with Scribble PDZ domains

Abstract

The cell polarity regulator Scribble has been shown to be a critical regulator of the establishment and development of tissue architecture, and its dysregulation promotes or suppresses tumor development in a context dependent manner. Scribble activity is subverted by numerous viruses. This includes human papillomaviruses (HPVs), who target Scribble via the E6 protein. Binding of E6 from high-risk HPV strains to Scribble via a C-terminal PDZ binding motif leads to Scribble degradation in vivo. However, the precise molecular basis for Scribble-E6 interactions remains to be defined. We now show that Scribble PDZ1 and PDZ3 are the major interactors of HPV E6 from multiple high-risk strains, with each E6 protein displaying a unique interaction profile. We then determined crystal structures of Scribble PDZ1 and PDZ3 domains in complex with the PBM motifs of E6 from HPV strains 16, 18 and 66. Our findings reveal distinct interaction patterns for each E6 PBM motif from a given HPV strain, suggesting that a complex molecular interplay exists that underpins the overt Scribble-HPV E6 interaction and controls E6 carcinogenic potential.

Viral subversion of the cell polarity regulator Scribble

“…To date, ETQL has been shown via GST-pull downs to bind to individual PDZ1, 3 and 4 domains of Scribble but not to PDZ2 [ 81 ]. However, a recent study [ 27 ] demonstrated that ETQL and ETQV binds to individual PDZ1, 2 and 3 but not PDZ4 domains using ITC, The differences in experimental methodologies and constructs may underpin the discrepancies with reported finding. Strikingly, an increase in the number of PDZ domains targeted by E6 correlates to an increase in E6 cancer-causing potential, with HPV-16 and HPV-18 PBMs featuring the most promiscuity with respect to their PDZ domain target selection [ 82 ].…”