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

Airah Javorsky,Marc Kvansakul,Patrick O Humbert

doi:10.1038/s42003-021-02250-7

Airah Javorsky, Marc Kvansakul + Show 1 more

Open Access

https://doi.org/10.1038/s42003-021-02250-7

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Abstract

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex. We show that C-terminal PDZ binding motifs of SARS-CoV-1 and SARS-CoV-2 E proteins bind the PALS1 PDZ domain with 29.6 and 22.8 μM affinity, whereas the related sequence from MERS-CoV did not bind. We then determined crystal structures of PALS1 PDZ domain bound to both SARS-CoV-1 and SARS-CoV-2 E protein PDZ binding motifs. Our findings establish the structural basis for SARS-CoV-1/2 mediated subversion of Crumbs polarity signalling and serve as a platform for the development of small molecule inhibitors to suppress SARS-CoV-1/2 mediated disruption of polarity signalling in epithelial cells.

Highlights

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure
NMR studies revealed that peptides covering the central transmembrane region of SARS-CoV-1 E protein oligomerize in lyso-myristoyl phosphatidylglycerol (LMPG) micelles to form pentameric ion channels[10,11], whereas the C-terminal tail was shown to harbour a binding motif sequence that allows binding to PDZ (postsynaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein) domains, an 80–90 amino acid structural domain commonly found in signalling proteins[12]
We report interaction and crystallographic studies examining the binding of Coronavirus E protein PDZ-binding motifs to the human PALS1 PDZ domain

Summary

Introduction

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. The SARS-CoV-1 E protein’s PDZ-binding motif[13] sequence allows interaction with the host cell polarity signalling protein PALS1 (Protein associated with Lin7/MPP5) interfering with epithelial function and integrity, a property of the SARS-CoV-1 E protein which is thought to be important for its virulence[13]. The CRB3 protein is the major crumbs isoforms expressed in human epithelial cells with the CRB3A splice form encoding the carboxy-terminal PBM sequence ERLI that enables PALS1 binding[24].

Results

Conclusion