Binding of interferon reduces the force of unfolding for interferon receptor 1

Chuartzman, Silvia; Nevo, Reinat; Waichman, Sharon; Shental, Dalit; Piehler, Jacob; Levy, Yaakov; Reich, Ziv; Kapon, Ruti

doi:10.1371/journal.pone.0175413

Cited by 5 publications

(3 citation statements)

References 59 publications

(72 reference statements)

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“…Because the interaction undergoes conformational changes upon ligand binding (Strunk et al, 2008; Chuartzman et al, 2017), we explored the binding kinetics of each ligand with AR1Fc using a two-state reaction model (Thomas et al, 2011). Similarly, again the sensorgrams gave a poor-fit to the Langmuir binding model (Supplementary Figures S1B,C).…”

Section: Resultsmentioning

confidence: 99%

A Glycoengineered Interferon-β Mutein (R27T) Generates Prolonged Signaling by an Altered Receptor-Binding Kinetics

et al. 2019

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The glycoengineering approach is used to improve biophysical properties of protein-based drugs, but its direct impact on binding affinity and kinetic properties for the glycoengineered protein and its binding partner interaction is unclear. Type I interferon (IFN) receptors, composed of IFNAR1 and IFNAR2, have different binding strengths, and sequentially bind to IFN in the dominant direction, leading to activation of signals and induces a variety of biological effects. Here, we evaluated receptor-binding kinetics for each state of binary and ternary complex formation between recombinant human IFN-β-1a and the glycoengineered IFN-β mutein (R27T) using the heterodimeric Fc-fusion technology, and compared biological responses between them. Our results have provided evidence that the additional glycan of R27T, located at the binding interface of IFNAR2, destabilizes the interaction with IFNAR2 via steric hindrance, and simultaneously enhances the interaction with IFNAR1 by restricting the conformational freedom of R27T. Consequentially, altered receptor-binding kinetics of R27T in the ternary complex formation led to a substantial increase in strength and duration of biological responses such as prolonged signal activation and gene expression, contributing to enhanced anti-proliferative activity. In conclusion, our findings reveal N-glycan at residue 25 of R27T is a crucial regulator of receptor-binding kinetics that changes biological activities such as long-lasting activation. Thus, we believe that R27T may be clinically beneficial for patients with multiple sclerosis.

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Section: Resultsmentioning

confidence: 99%

A Glycoengineered Interferon-β Mutein (R27T) Generates Prolonged Signaling by an Altered Receptor-Binding Kinetics

et al. 2019

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“…IFNAR1 binding is associated with a major conformational change involving movement within the four extracellular SD domains, resulting in the efficient capping of IFN molecule ( 74 , 75 ). IFN binding has also been shown to reduce the force needed to unfold the IFNAR1 extracellular domains ( 76 ). The reduction in IFNAR1 rigidity would enable the propagation of IFN-induced conformational changes closer to or even across the PM.…”

Section: The Basic Interferon—type I Interferon Receptor Complexmentioning

confidence: 99%

Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads

et al. 2021

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Like most plasma membrane proteins, type I interferon (IFN) receptor (IFNAR) traffics from the outer surface to the inner compartments of the cell. Long considered as a passive means to simply control subunits availability at the plasma membrane, an array of new evidence establishes IFNAR endocytosis as an active contributor to the regulation of signal transduction triggered by IFN binding to IFNAR. During its complex journey initiated at the plasma membrane, the internalized IFNAR complex, i.e. IFNAR1 and IFNAR2 subunits, will experience post-translational modifications and recruit specific effectors. These finely tuned interactions will determine not only IFNAR subunits destiny (lysosomal degradation vs. plasma membrane recycling) but also the control of IFN-induced signal transduction. Finally, the IFNAR system perfectly illustrates the paradigm of the crosstalk between membrane trafficking and intracellular signaling. Investigating the complexity of IFN receptor intracellular routes is therefore necessary to reveal new insight into the role of IFNAR membrane dynamics in type I IFNs signaling selectivity and biological activity.

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“…Upon ligand binding, IFNAR1 undergoes a loss in mechanical stability, manifested as cooperative movements between IFNAR1‐SD2 and SD3 106,107 and a multistep conformational change that is propagated along the receptor 60 . Both the loss in mechanical stability and the conformational change are required for effective signal transduction 60,106,107 .…”

Section: Role Of Ifnars In Human Diseasementioning

confidence: 99%

Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal

Weerd

Vivian

Lim

et al. 2020

Journal of Leukocyte Biology

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The type I IFNs activate an array of signaling pathways, which are initiated after IFNs bind their cognate receptors, IFNα/β receptor (IFNAR)1 and IFNAR2. These signals contribute to many aspects of human health including defense against pathogens, cancer immunosurveillance, and regulation of inflammation. How these cytokines interact with their receptors influences the quality of these signals. As such, the integrity of receptor structure is pivotal to maintaining human health and the response to immune stimuli. This review brings together genome wide association studies and clinical reports describing the association of nonsynonymous IFNAR1 and IFNAR2 polymorphisms with clinical disease, including altered susceptibility to viral and bacterial pathogens, autoimmune diseases, cancer, and adverse reactions to live‐attenuated vaccines. We describe the amino acid substitutions or truncations induced by these polymorphisms and, using the knowledge of IFNAR conformational changes, IFNAR‐IFN interfaces and overall structure‐function relationship of the signaling complexes, we hypothesize the effect of these polymorphisms on receptor structure. That these predicted changes to IFNAR structure are associated with clinical manifestations of human disease, highlights the importance of IFNAR structural integrity to maintaining functional quality of these receptor‐mediated responses. Type I IFNs are pivotal to innate immune responses and ultimately, to human health. Understanding the consequences of altered structure on the actions of these clinically significant cell receptors provides important information on the roles of IFNARs in health and disease.

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Binding of interferon reduces the force of unfolding for interferon receptor 1

Cited by 5 publications

References 59 publications

A Glycoengineered Interferon-β Mutein (R27T) Generates Prolonged Signaling by an Altered Receptor-Binding Kinetics

A Glycoengineered Interferon-β Mutein (R27T) Generates Prolonged Signaling by an Altered Receptor-Binding Kinetics

Interferon Receptor Trafficking and Signaling: Journey to the Cross Roads

Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal

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