SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex. We show that C-terminal PDZ binding motifs of SARS-CoV-1 and SARS-CoV-2 E proteins bind the PALS1 PDZ domain with 29.6 and 22.8 μM affinity, whereas the related sequence from MERS-CoV did not bind. We then determined crystal structures of PALS1 PDZ domain bound to both SARS-CoV-1 and SARS-CoV-2 E protein PDZ binding motifs. Our findings establish the structural basis for SARS-CoV-1/2 mediated subversion of Crumbs polarity signalling and serve as a platform for the development of small molecule inhibitors to suppress SARS-CoV-1/2 mediated disruption of polarity signalling in epithelial cells. Airah Javorsky et al. present the crystal structures of SARS-CoV-1 and SARS-CoV-2 E proteins in complex with the PALS1 PDZ domain. Their results suggest that the coronavirus E protein can interfere with normal PALS1 binding, potentially disrupting epithelial tissue integrity, and may provide future insight into the development of small molecule inhibitors against SARS-CoV-1/2.
【저자키워드】 SARS-CoV-2, X-ray crystallography, 【초록키워드】 COVID-19, coronavirus disease, coronavirus, Respiratory failure, Pneumonia, SARS-COV-2 infection, SARS-CoV-1, MERS-CoV, E protein, epithelial cells, crystal structure, epithelial, platform, binding, motifs, PALS1, tissue, complex, domain, sequence, life-threatening, molecular basis, motif, Cell, interfere, suppress, C-terminal, disrupting, human epithelial cell, small molecule inhibitor, these symptom, 【제목키워드】 coronavirus, E protein, Interaction, PALS1, domain,