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Host PDZ-containing proteins targeted by SARS-CoV-2.

Célia Caillet-Saguy1, Fabien Durbesson2, Veronica V Rezelj3

  • 1Institut Pasteur, Unité Récepteurs-Canaux, UMR CNRS 3571, Paris, France.

The FEBS Journal
|April 17, 2021
PubMed
Summary

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins interact with human PDZ proteins, impacting viral replication. Identifying these SARS-CoV-2 protein interactions aids in understanding COVID-19 severity and developing antiviral therapies.

Keywords:
3A and NPDZ-binding motifPDZ-containing proteinSARS-CoV-2human PDZ libraryviral proteins Eviral replication

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Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes small linear motifs for protein interactions.
  • These motifs target protein interacting domains known as PSD-95/Dlg/ZO-1 (PDZ) domains, found at the C-terminus of viral proteins E, 3a, and N.

Purpose of the Study:

  • To identify human PDZ domain-containing proteins that bind to SARS-CoV-2 proteins E, 3a, and N.
  • To investigate the functional impact of these interactions on viral replication and potential therapeutic strategies.

Main Methods:

  • High-throughput affinity-profiling against the human PDZome.
  • Characterization of binding affinities (dissociation constants) for identified SARS-CoV-2 protein-PDZ interactions.
  • Gene knockdown experiments to assess the effect of host PDZ proteins on viral replication.

Main Results:

  • Sixteen human PDZ binders for SARS-CoV-2 proteins E, 3a, and N were identified, with dissociation constants ranging from 3 to 82 μm.
  • Six binders (TJP1, PTPN13, HTRA1, PARD3, MLLT4, LNX2) interact with both SARS-CoV and SARS-CoV-2 proteins.
  • Three binders (NHERF1, MAST2, RADIL) are specific to SARS-CoV-2 E protein.
  • Seven identified host PDZ proteins significantly affect viral replication upon knockdown.
  • Many identified PDZ partners are involved in cellular junctions/polarity and immune response evasion.

Conclusions:

  • PDZ profiling reveals critical host-PDZ interactions exploited by SARS-CoV-2.
  • These interactions are implicated in viral replication, pathogenesis, and immune evasion.
  • Understanding these targets provides avenues for developing novel anti-coronaviral therapeutics.