Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK

Dubrow, Alyssa; Lin, Shuai; Savage, Nowlan; Shen, Qingliang; Cho, Jaehyun

doi:10.3390/v12030338

Cited by 9 publications

(10 citation statements)

References 50 publications

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“…Considering the reasonably high ϕ-values of Y89 and D101, the specific binding orientation seems to be well-defined at the TS ( Supplementary Figure 2 ). Interestingly, we previously showed that the 1918NS1:p85β interaction is not significantly affected by a high salt concentration ( Dubrow et al, 2020 ). Although this seems contrasting with the result of D101A, the difference is reconciled by considering that the ϕ-value is a relative parameter.…”

Section: Resultsmentioning

confidence: 99%

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

Dubrow

Kim

Topo

et al. 2021

Front. Mol. Biosci.

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Biomolecular recognition often involves conformational changes as a prerequisite for binding (i.e., conformational selection) or concurrently with binding (i.e., induced-fit). Recent advances in structural and kinetic approaches have enabled the detailed characterization of protein motions at atomic resolution. However, to fully understand the role of the conformational dynamics in molecular recognition, studies on the binding transition state are needed. Here, we investigate the binding transition state between nonstructural protein 1 (NS1) of the pandemic 1918 influenza A virus and the human p85β subunit of PI3K. 1918 NS1 binds to p85β via conformational selection. We present the free-energy mapping of the transition and bound states of the 1918 NS1:p85β interaction using linear free energy relationship and ϕ-value analyses. We find that the binding transition state of 1918 NS1 and p85β is structurally similar to the bound state with well-defined binding orientation and hydrophobic interactions. Our finding provides a detailed view of how protein motion contributes to the development of intermolecular interactions along the binding reaction coordinate.

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Section: Resultsmentioning

confidence: 99%

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

Dubrow

Kim

Topo

et al. 2021

Front. Mol. Biosci.

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“…This is compatible with the X-ray crystal structure, as NS1 and p110 bind at opposite ends of p85. Additionally, NS1 proteins from some strains of influenza can form a heterotrimer with p85β and Crk proteins, discussed previously, in a manner that further enhances PI3K activation [ 133 , 198 ]. SH3 binding competent NS1 proteins were able to displace endogenous p85β-CrkL complexes and form a heterotrimer with NS1 as the bridge.…”

Section: Pi3kmentioning

confidence: 99%

Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins

Blake,

Kleinpeter,

Jureka

et al. 2023

Viruses

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The Influenza A virus is a continuous threat to public health that causes yearly epidemics with the ever-present threat of the virus becoming the next pandemic. Due to increasing levels of resistance, several of our previously used antivirals have been rendered useless. There is a strong need for new antivirals that are less likely to be susceptible to mutations. One strategy to achieve this goal is structure-based drug development. By understanding the minute details of protein structure, we can develop antivirals that target the most conserved, crucial regions to yield the highest chances of long-lasting success. One promising IAV target is the virulence protein non-structural protein 1 (NS1). NS1 contributes to pathogenicity through interactions with numerous host proteins, and many of the resulting complexes have been shown to be crucial for virulence. In this review, we cover the NS1-host protein complexes that have been structurally characterized to date. By bringing these structures together in one place, we aim to highlight the strength of this field for drug discovery along with the gaps that remain to be filled.

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“…We then sought to determine which viral protein is responsible for the stimulation of YAP/ TAZ activities. Since several literature has pointed out IAV NS1 could affect host cell signaling and control cellular processes such as activation of PI3K signaling [31,32], we hypothesized that that NS1 is responsible for the regulation of YAP/TAZ activities. Therefore, we transfected A549 cells with Flag tagged NS1 protein from PR8 virus, together with the luciferase reporter plasmids of CTGF or GTIIC.…”

Section: Iav Ns1 Binds To Yap/taz To Stimulate Their Activitiesmentioning

confidence: 99%

Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response

Zhang

Lei

et al. 2022

PLoS Pathog

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The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could activate the Hippo effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through physical binding of the IAV non-structural protein 1 (NS1) with C-terminal domain of YAP/TAZ, facilitating their nuclear location. Meanwhile, YAP/TAZ downregulated the expression of pro-inflammatory and anti-viral cytokines against IAV infection, therefore benefiting virus replication and host cell apoptosis. A mouse model of IAV infection further demonstrated Yap deficiency protected mice against IAV infection, relieving lung injury. Mechanistically, YAP/TAZ blocked anti-viral innate immune signaling via downregulation of Toll-like receptor 3 (TLR3) expression. YAP directly bound to the putative TEADs binding site on the promoter region of TLR3. The elimination of acetylated histone H3 occupancy in the TLR3 promoter resulted in its transcriptional silence. Moreover, treatment of Trichostatin A, a histone deacetylases (HDACs) inhibitor or disruption of HDAC4/6 reversed the inhibition of TLR3 expression by YAP/TAZ, suggesting HDAC4/6 mediated the suppression function of YAP/TAZ. Taken together, we uncovered a novel immunomodulatory mechanism employed by IAV, where YAP/TAZ antagonize TLR3-mediated innate immunity.

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Molecular Basis of the Ternary Interaction between NS1 of the 1918 Influenza A Virus, PI3K, and CRK

Cited by 9 publications

References 50 publications

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

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

Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins

Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response

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