Insights into the molecular recognition of the second PDZ domain of ZO1 by coronavirus Envelope-derived peptides

The Envelope (E) protein, one of the structural proteins encoded by coronavirus (CoV) genome, is involved in multiple processes of the virus life cycle and directly related to the pathogenesis process. The C-terminus of E contains an important virulence factor, a PDZ domain binding motif (PBM), whose deletion or modification is sufficient to attenuate the virus. Notably, the PBM of E interacts with the second PDZ domain (PDZ2) of host Zonula Occludens 1 protein (ZO1), leading to delayed formation of tight junctions (TJs) and disruption of the respiratory epithelium. Although the binding reaction between ZO1-PDZ2 and E has been extensively studied since COVID-19 pandemic breakout, the structural determinants governing the binding process of ZO1-PDZ2 by E protein are still poorly understood. In this scenario, we performed a comparative study through a combination of experimental NMR and computational methods to structurally characterize the interaction occurring between ZO1-PDZ2 and three peptides mimicking the C-terminal PBM of E protein from SARS-CoV (now SARS-CoV-1), SARS-CoV-2, and MERS-CoV. Our results could provide the basis for the development of therapeutic strategies that may reduce cell damage and the morbidity and mortality associated with coronavirus infection.