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Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses.


ABSTRACT: The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85? subunit. Here we present the mechanism underlying the molecular recognition of the p85? subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85? of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1ED) undergoes a conformational change to bind p85?. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1ED exists in a dynamic equilibrium between p85?-binding-competent and -incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1ED proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85?. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1ED can result in the faster hijacking of p85? compared to Ud NS1ED, although the former has a lower affinity to p85? than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.

SUBMITTER: Cho JH 

PROVIDER: S-EPMC7104383 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses.

Cho Jae-Hyun JH   Zhao Baoyu B   Shi Jie J   Savage Nowlan N   Shen Qingliang Q   Byrnes James J   Yang Lin L   Hwang Wonmuk W   Li Pingwei P  

Proceedings of the National Academy of Sciences of the United States of America 20200309 12


The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85β subunit. Here we present the mechanism underlying the molecular recognition of the p85β subunit by 1918 N  ...[more]

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