Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection

Catching BETs by viruses

“…In 2020, BRD2 and BRD4 were identified as potential interactors of the envelope (E) protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) [29] . Two years later the direct interaction between human BRD4 and the E protein of SARS-CoV-2 has been confirmed experimentally [30] , [31] . The SARS-CoV-2 E protein contains only two lysine residues, K53 and K63, located in the C-terminus of the protein ( Fig.…”

“…The BD-binding sites (acetylated lysine residues) and the ET-binding site are highlighted in red. (e) A ribbon diagram of the crystal structure of BRD4 BD1 (blue and yellow) in complex with the SARS-CoV-2 E peptide diacetylated at K53 and K63 (red) (PDB ID: 7TV0 ) [30] . …”

“…1 d). In their recent work, Vann et al demonstrate that human histone acetyltransferase (HAT) p300 and to a lesser degree the MYST-family HAT complexes can acetylate the SARS-CoV-2 E peptide and that full-length SARS-CoV-2 E protein expressed in 293 T cells is acetylated and forms complex with BRD4 [30] . Both BD1 and BD2 of BRD4 interact with diacetylated K53ac/K63ac E peptide, exhibiting a 30–40 μM binding affinity, but bind weaker to mono-acetylated E peptides.…”

“…The crystal structure of BRD4 BD1 in complex with the diacetylated K53ac/K63ac E peptide reveals that two molecules of BD1 capture one E peptide [30] ( Fig. 1 e).…”

“…Interestingly, the same region of the homologous E protein from SARS-CoV exists in an α-helical conformation even in an apo-state of the protein [32] . In addition to the acetyllysine-dependent association with BRD4, the SFYVYSRVK(63)NLN region of the SARS-CoV-2 E protein was found to interact with the ET domain of BRD4 in an acetyllysine independent manner [30] .…”