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Article

Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble

1
Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
2
Research Centre for Molecular Cancer Prevention, La Trobe University, Melbourne, VIC 3086, Australia
3
Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, VIC 3010, Australia
4
Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
*
Authors to whom correspondence should be addressed.
Academic Editor: Hualan Chen
Viruses 2022, 14(3), 583; https://doi.org/10.3390/v14030583
Received: 31 January 2022 / Revised: 3 March 2022 / Accepted: 9 March 2022 / Published: 11 March 2022
(This article belongs to the Section Human Virology and Viral Diseases)
Scribble is a highly conserved regulator of cell polarity, a process that enables the generation of asymmetry at the cellular and tissue level in higher organisms. Scribble acts in concert with Disc-large (Dlg) and Lethal-2-giant larvae (Lgl) to form the Scribble polarity complex, and its functional dysregulation is associated with poor prognosis during viral infections. Viruses have been shown to interfere with Scribble by targeting Scribble PDZ domains to subvert the network of interactions that enable normal control of cell polarity via Scribble, as well as the localisation of the Scribble module within the cell. The influenza A virus NS1 protein was shown to bind to human Scribble (SCRIB) via its C-terminal PDZ binding motif (PBM). It was reported that the PBM sequence ESEV is a virulence determinant for influenza A virus H5N1 whilst other sequences, such as ESKV, KSEV and RSKV, demonstrated no affinity towards Scribble. We now show, using isothermal titration calorimetry (ITC), that ESKV and KSEV bind to SCRIB PDZ domains and that ESEV unexpectedly displayed an affinity towards all four PDZs and not just a selected few. We then define the structural basis for the interactions of SCRIB PDZ1 domain with ESEV and ESKV PBM motifs, as well as SCRIB PDZ3 with the ESKV PBM motif. These findings will serve as a platform for understanding the role of Scribble PDZ domains and their interactions with different NS1 PBMs and the mechanisms that mediate cell polarity within the context of the pathogenesis of influenza A virus. View Full-Text
Keywords: Influenza A virus; bird-flu; H5N1; cell polarity; X-ray crystallography; isothermal titration calorimetry; NS1; PDZ; scribble Influenza A virus; bird-flu; H5N1; cell polarity; X-ray crystallography; isothermal titration calorimetry; NS1; PDZ; scribble
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MDPI and ACS Style

Javorsky, A.; Humbert, P.O.; Kvansakul, M. Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble. Viruses 2022, 14, 583. https://doi.org/10.3390/v14030583

AMA Style

Javorsky A, Humbert PO, Kvansakul M. Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble. Viruses. 2022; 14(3):583. https://doi.org/10.3390/v14030583

Chicago/Turabian Style

Javorsky, Airah, Patrick O. Humbert, and Marc Kvansakul. 2022. "Structural Basis of the Avian Influenza NS1 Protein Interactions with the Cell Polarity Regulator Scribble" Viruses 14, no. 3: 583. https://doi.org/10.3390/v14030583

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