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Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain

Airah Javorsky1, Patrick O Humbert2,3,4,5, Marc Kvansakul6,7

  • 1Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Vic, Australia.

Communications Biology
|June 12, 2021
PubMed

Insights

The SARS-CoV-2 E protein disrupts human epithelial cell polarity by binding to PALS1. This structural understanding aids in developing inhibitors against viral-induced respiratory failure in COVID-19.

Area of Science:

  • Molecular biology
  • Virology
  • Cell biology

Background:

  • SARS-CoV-2 causes COVID-19, leading to pneumonia and respiratory failure.
  • The molecular mechanisms underlying these severe symptoms are not fully understood.
  • Viral proteins can interfere with host cell functions, contributing to disease pathogenesis.

Purpose of the Study:

  • To investigate the molecular interaction between SARS-CoV-2 E protein and host cell polarity factors.
  • To elucidate the structural basis of this interaction.
  • To provide a foundation for developing therapeutic interventions.

Main Methods:

  • Co-crystallography to determine the structure of PALS1 PDZ domain bound to viral E protein motifs.
  • Biochemical assays to measure binding affinity (Kd) between viral E protein motifs and PALS1 PDZ domain.
  • Sequence analysis of related coronaviruses (MERS-CoV).

Main Results:

  • SARS-CoV-1 and SARS-CoV-2 E proteins bind to the PALS1 PDZ domain with high affinity (29.6 and 22.8 μM, respectively).
  • Crystal structures reveal the atomic details of E protein binding to the PALS1 PDZ domain.
  • MERS-CoV E protein sequence did not bind to PALS1 PDZ domain, indicating specificity.

Conclusions:

  • The E proteins of SARS-CoV-1 and SARS-CoV-2 subvert host cell polarity signaling by targeting the Crumbs complex via PALS1.
  • The determined structures provide a molecular basis for understanding viral pathogenesis.
  • These findings offer a platform for designing small molecule inhibitors to block E protein-PALS1 interactions and mitigate COVID-19 symptoms.

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