Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

Li, Hongchun; Sharma, Nanaocha; General, Ignacio J.; Schreiber, Gideon; Bahar, İvet

doi:10.1016/j.jmb.2017.06.011

Cited by 17 publications

(17 citation statements)

References 61 publications

(87 reference statements)

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“…Besides the close conformation, the salt-bridge interaction also participates in supporting a metastable extended ST2 ECD conformation observed in the ST2 3 simulation. Modulation of the receptor conformation by interdomain interaction has recently been demonstrated by the study of Li et al 82 . Q268 and Q328 in subdomain 3 and 4 in type I interferon receptor (IFNAR1) was hypothesized to be in close location because of conformational flexibility based on modeling.…”

Section: Discussionmentioning

confidence: 90%

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Yang

2020

Sci Rep

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Cytokine receptors receive extracellular cues by binding with cytokines to transduce a signaling cascade leading to gene transcription in cells. Their soluble isoforms, functioning as decoy receptors, contain only the ectodomain. Whether the ectodomains of cytokine receptors at the membrane exhibit different conformational dynamics from their soluble forms is unknown. Using Stimulation-2 (ST2) as an example, we performed microsecond molecular dynamics (MD) simulations to study the conformational dynamics of the soluble and the membrane-bound ST2 (sST2 and ST2). Combined use of accelerated and conventional MD simulations enabled extensive sampling of the conformational space of sST2 for comparison with ST2. Using the interdomain loop conformation as the reaction coordinate, we built a Markov State Model to determine the slowest implied timescale of the conformational transition in sST2 and ST2. We found that the ectodomain of ST2 undergoes slower conformational relaxation but exhibits a faster rate of conformational transition in a more restricted conformational space than sST2. Analyses of the relaxed conformations of ST2 further suggest important contributions of interdomain salt-bridge interactions to the stabilization of different ST2 conformations. Our study elucidates differential conformational properties between sST2 and ST2 that may be exploited for devising strategies to selectively target each isoform.

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Section: Discussionmentioning

confidence: 90%

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Yang

2020

Sci Rep

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“…Consistent with our findings in Ifnar−/− mice, and confirming the importance of IFNAR on RSV infection, we found that the IFNAR1 rs2257167 C allele (a valine to leucine substitution in the SD2 domain) was associated with protection against severe disease in RSV-positive infants. The IFNAR1 SD2 and SD3 interface contains a hinge center that mediates movement of the two halves upon ligand engagement 46,47 . Structural modeling revealed the larger leucine residue provides a stable conformation with better packing in the hydrophobic SD2 cavity 39 .…”

Section: Discussionmentioning

confidence: 99%

Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response

et al. 2019

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Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-β (IFN-β) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-β response. The effect of acetate on RSV infection was abolished in Gpr43 − / − mice. Our findings reveal antiviral effects of acetate involving IFN-β in lung epithelial cells and engagement of GPR43 and IFNAR.

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“…Although the IFN ligand binds largely to the hinge region between the IFNAR1 SD2 and SD3 domains, the NTD of IFNAR1 (ie, SD1) moves downwards ~10 Å to interact with the IFN ligand, further securing it to IFNAR1. The high mobility of IFNAR1 is required for optimal ligand binding and the formation of a ternary complex that then initiates trans-phosphorylation between JAK1 and TYK2 28 .…”

Section: Discussionmentioning

confidence: 99%

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

et al. 2018

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The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.

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Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

Cited by 17 publications

References 61 publications

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

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