1. Interaction between SARS-CoV PBM and Cellular PDZ Domains Leading to Virus Virulence.
- Author
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Honrubia JM, Valverde JR, Muñoz-Santos D, Ripoll-Gómez J, de la Blanca N, Izquierdo J, Villarejo-Torres M, Marchena-Pasero A, Rueda-Huélamo M, Nombela I, Ruiz-Yuste M, Zuñiga S, Sola I, and Enjuanes L
- Subjects
- Humans, Virulence, Animals, Viroporin Proteins metabolism, Viroporin Proteins genetics, COVID-19 virology, Chlorocebus aethiops, Vero Cells, Amino Acid Motifs, Severe acute respiratory syndrome-related coronavirus genetics, Severe acute respiratory syndrome-related coronavirus pathogenicity, Severe acute respiratory syndrome-related coronavirus metabolism, Virus Replication, PDZ Domains, SARS-CoV-2 pathogenicity, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, SARS-CoV-2 physiology, Protein Binding, Coronavirus Envelope Proteins metabolism, Coronavirus Envelope Proteins genetics
- Abstract
The interaction between SARS-CoV PDZ-binding motifs (PBMs) and cellular PDZs is responsible for virus virulence. The PBM sequence present in the 3a and envelope (E) proteins of SARS-CoV can potentially bind to over 400 cellular proteins containing PDZ domains. The role of SARS-CoV 3a and E proteins was studied. SARS-CoVs, in which 3a-PBM and E-PMB have been deleted (3a-PBM-/E-PBM-), reduced their titer around one logarithmic unit but still were viable. In addition, the absence of the E-PBM and the replacement of 3a-PBM with that of E did not allow the rescue of SARS-CoV. E protein PBM was necessary for virulence, activating p38-MAPK through the interaction with Syntenin-1 PDZ domain. However, the presence or absence of the homologous motif in the 3a protein, which does not bind to Syntenin-1, did not affect virus pathogenicity. Mutagenesis analysis and in silico modeling were performed to study the extension of the PBM of the SARS-CoV E protein. Alanine and glycine scanning was performed revealing a pair of amino acids necessary for optimum virus replication. The binding of E protein with the PDZ2 domain of the Syntenin-1 homodimer induced conformational changes in both PDZ domains 1 and 2 of the dimer.
- Published
- 2024
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