tetano
Editor, Senior Moderator
Front Microbiol
. 2022 Feb 23;13:829094.
doi: 10.3389/fmicb.2022.829094. eCollection 2022.
Interactions of Severe Acute Respiratory Syndrome Coronavirus 2 Protein E With Cell Junctions and Polarity PSD-95/Dlg/ZO-1-Containing Proteins
Yanlei Zhu[SUP] 1 [/SUP], Flavio Alvarez[SUP] 1 [/SUP], Nicolas Wolff[SUP] 1 [/SUP], Ariel Mechaly[SUP] 2 [/SUP], Sébastien Brûlé[SUP] 3 [/SUP], Benoit Neitthoffer[SUP] 4 [/SUP], Sandrine Etienne-Manneville[SUP] 4 [/SUP], Ahmed Haouz[SUP] 2 [/SUP], Batiste Boëda[SUP] 4 [/SUP], Célia Caillet-Saguy[SUP] 1 [/SUP]
Affiliations
Abstract
The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ-binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains, which is identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified 10 human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, and LNX2) and MPP5/PALS1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2, and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4, and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in the E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.
Keywords: PDZ-binding motif; PDZ-containing protein; SARS-CoV-2; cell junctions and polarity; envelope protein; host–pathogen interactions; protein–protein interaction.
. 2022 Feb 23;13:829094.
doi: 10.3389/fmicb.2022.829094. eCollection 2022.
Interactions of Severe Acute Respiratory Syndrome Coronavirus 2 Protein E With Cell Junctions and Polarity PSD-95/Dlg/ZO-1-Containing Proteins
Yanlei Zhu[SUP] 1 [/SUP], Flavio Alvarez[SUP] 1 [/SUP], Nicolas Wolff[SUP] 1 [/SUP], Ariel Mechaly[SUP] 2 [/SUP], Sébastien Brûlé[SUP] 3 [/SUP], Benoit Neitthoffer[SUP] 4 [/SUP], Sandrine Etienne-Manneville[SUP] 4 [/SUP], Ahmed Haouz[SUP] 2 [/SUP], Batiste Boëda[SUP] 4 [/SUP], Célia Caillet-Saguy[SUP] 1 [/SUP]
Affiliations
- PMID: 35283834
- PMCID: PMC8909127
- DOI: 10.3389/fmicb.2022.829094
Abstract
The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ-binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains, which is identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified 10 human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, and LNX2) and MPP5/PALS1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2, and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4, and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in the E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.
Keywords: PDZ-binding motif; PDZ-containing protein; SARS-CoV-2; cell junctions and polarity; envelope protein; host–pathogen interactions; protein–protein interaction.