Structural basis for SARS-CoV-2 envelope protein recognition of human cell junction protein PALS1

• DOI: 10.1038/s41467-021-23533-x
• Publication Date: 2021-06-08T10:07:47Z
• Authors: Jin Chai; Yuanheng Cai; Changxu Pang; Liguo Wang; Sean McSweeney; John Shanklin; Qun Liu
• Keywords: 0301 basic medicine; 0303 health sciences; SARS-CoV-2; Science; Q; Cryoelectron Microscopy; Membrane Proteins; Article; 3. Good health; Coronavirus Envelope Proteins; Structure-Activity Relationship; 03 medical and health sciences; Intercellular Junctions; Protein Domains; Structural Homology, Protein; Humans; Amino Acid Sequence; Nucleoside-Phosphate Kinase

AbstractThe COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created global health and economic emergencies. SARS-CoV-2 viruses promote their own spread and virulence by hijacking human proteins, which occurs through viral protein recognition of human targets. To understand the structural basis for SARS-CoV-2 viral-host protein recognition, here we use cryo-electron microscopy (cryo-EM) to determine a complex structure of the human cell junction protein PALS1 and SARS-CoV-2 viral envelope (E) protein. Our reported structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains of PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce E-mediated virulence.