Détail du document
Identifiant
oai:pubmedcentral.nih.gov:1114...
Sujet
ArticleAuteur
Gonzales, James Kim, Iktae Hwang, Wonmuk Cho, Jae-HyunLangue
enEditeur
Cold Spring Harbor Laboratory
Catégorie
biorxiv
Année
2024
Date de référencement
05/06/2024
Mots clés
pr8 analysis affinity epistasis virus p85β influenza dynamic communications long-range mutations ns1 allostericRésumé
Viral proteins frequently mutate to evade or antagonize host innate immune responses, yet the impact of these mutations on the molecular energy landscape remains unclear.
Epistasis, the intramolecular communications between mutations, often renders the combined mutational effects unpredictable.
Nonstructural protein 1 (NS1) is a major virulence factor of the influenza A virus (IAV) that activates host PI3K by binding to its p85β subunit.
Here, we present the deep analysis for the impact of evolutionary mutations in NS1 that emerged between the 1918 pandemic IAV strain and its descendant PR8 strain.
Our analysis reveal how the mutations rewired inter-residue communications which underlies long-range allosteric and epistatic networks in NS1.
Our findings show that PR8 NS1 binds to p85β with approximately 10-fold greater affinity than 1918 NS1 due to allosteric mutational effects.
Notably, these mutations also exhibited long-range epistatic effects.
NMR chemical shift perturbation and methyl-axis order parameter analyses revealed that the mutations induced long-range structural and dynamic changes in PR8 NS1, enhancing its affinity to p85β.
Complementary MD simulations and graph-based network analysis uncover how these mutations rewire dynamic residue interaction networks, which underlies the long-range epistasis and allosteric effects on p85β-binding affinity.
Significantly, we find that conformational dynamics of residues with high betweenness centrality play a crucial role in communications between network communities and are highly conserved across influenza A virus evolution.
These findings advance our mechanistic understanding of the allosteric and epistatic communications between distant residues and provides insight into their role in the molecular evolution of NS1.
Gonzales, James,Kim, Iktae,Hwang, Wonmuk,Cho, Jae-Hyun, 2024, Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of influenza A virus, Cold Spring Harbor Laboratory
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