ArticleProceedings of the National Academy of Sciences of the United States of America2010
Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 112 citations in OpenAlex.
- Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Molecular Basis of Oncogenic PI3K Proteins.Cancers · 2024Review
- Proline, a unique amino acid whose polymer, polyproline II helix, and its analogues are involved in many biological processes: a review.Amino acids · 2024Review
- Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins.Viruses · 2023Review
- Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1-Host Interactions as Antiviral Targets for Flu.International journal of molecular sciences · 2023Article
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- New substitutions on NS1 protein from influenza A (H1N1) virus: Bioinformatics analyses of Indian strains isolated from 2009 to 2020.Health science reports · 2022Article
- Suppressing Nonspecific Binding in Biolayer Interferometry Experiments for Weak Ligand-Analyte Interactions.ACS omega · 2022Article
- Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells.Genes & development · 2022Review
- Review
- Role of the Chaperone Protein 14-3-3ε in the Regulation of Influenza A Virus-Activated Beta Interferon.Journal of virology · 2021Article
- The Two Sides of the Same Coin-Influenza Virus and Intracellular Signal Transduction.Cold Spring Harbor perspectives in medicine · 2021Review
- Understanding the Binding Transition State After the Conformational Selection Step: The Second Half of the Molecular Recognition Process Between NS1 of the 1918 Influenza Virus and Host p85β.Frontiers in molecular biosciences · 2021Article
- Article
- Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK.Viruses · 2020Article
- The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection.International journal of molecular sciences · 2020Review
- Differential Modulation of Innate Immune Responses in Human Primary Cells by Influenza A Viruses Carrying Human or Avian Nonstructural Protein 1.Journal of virology · 2019Article
- Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1.Journal of virology · 2019Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Seasonal epidemics and periodic worldwide pandemics caused by influenza A viruses are of continuous concern. The viral nonstructural (NS1) protein is a multifunctional virulence factor that antagonizes several host innate immune defenses during infection. NS1 also directly stimulates class IA phosphoinositide 3-kinase (PI3K) signaling, an essential cell survival pathway commonly mutated in human cancers. Here, we present a 2.3-A resolution crystal structure of the NS1 effector domain in complex with the inter-SH2 (coiled-coil) domain of p85beta, a regulatory subunit of PI3K. Our data emphasize the remarkable isoform specificity of this interaction, and provide insights into the mechanism by which NS1 activates the PI3K (p85beta:p110) holoenzyme. A model of the NS1:PI3K heterotrimeric complex reveals that NS1 uses the coiled-coil as a structural tether to sterically prevent normal inhibitory contacts between the N-terminal SH2 domain of p85beta and the p110 catalytic subunit. Furthermore, in this model, NS1 makes extensive contacts with the C2/kinase domains of p110, and a small acidic alpha-helix of NS1 sits adjacent to the highly basic activation loop of the enzyme. During infection, a recombinant influenza A virus expressing NS1 with charge-disruption mutations in this acidic alpha-helix is unable to stimulate the production of phosphatidylinositol 3,4,5-trisphosphate or the phosphorylation of Akt. Despite this, the charge-disruption mutations in NS1 do not affect its ability to interact with the p85beta inter-SH2 domain in vitro. Overall, these data suggest that both direct binding of NS1 to p85beta (resulting in repositioning of the N-terminal SH2 domain) and possible NS1:p110 contacts contribute to PI3K activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.