Differential Receptor Subunit Affinities of Type I Interferons Govern Differential Signal Activation

Jaks, Eva; Gavutis, Martynas; Uzé, Gilles; Martal, J.; Piehler, Jacob

doi:10.1016/j.jmb.2006.11.053

Cited by 199 publications

(201 citation statements)

References 44 publications

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“…Similar effects, mediated by multivalent connector proteins (known as ''scaffold'' or ''prozone'' effect) have been implicated in cross-talk prevention in MAPK cascades (23), paradoxical function of Cdk-binding proteins (24), and others (25)(26)(27). The effect was also noticed in numerical simulations of Type I Interferon receptor dimerization (14), and there is evidence that it occurs in signaling by Erythropoietin through its homodimeric receptor (28).…”

Section: Nonmonotonic Dose Response Curvementioning

confidence: 77%

“…2 is very different from that of the monomeric receptor, and is shown in Fig. 2 for typical values of the parameters (10,14,22). First, the number of ternary complexes is nonmonotonic in the ligand concentration and reaches a maximum T max at the concentration C Ã ¼ ffiffiffiffiffiffiffiffiffiffi ffi…”

Section: Nonmonotonic Dose Response Curvementioning

confidence: 94%

“…Although it is clear that the discrimination at least partially relies on the differences in ligand binding affinity to the receptor (10)(11)(12)14), that alone is not always sufficient for distinguishing between different ligands. Indeed, in the classical view of (monomeric) receptor signaling, the receptor occupancy, which dictates the signaling strength, is…”

Section: Mathematical Description Of Receptor Bindingmentioning

confidence: 99%

“…2. Ligand-induced dimerization can occur via two parallel pathways (14). A ligand molecule L can first bind and form a binary complex with either of the two receptor subunits, denoted as R 1 and R 2 , respectively, with the corresponding binding onand off-rates k þ 1 ; k À 1 and k þ 2 ; k À 2 that define the corresponding equilibrium dissociation constants,…”

Section: Mathematical Description Of Receptor Bindingmentioning

confidence: 99%

See 3 more Smart Citations

Absolute Ligand Discrimination by Dimeric Signaling Receptors

Fathi

Nayak

Feld

et al. 2016

Biophysical Journal

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Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor.

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Section: Nonmonotonic Dose Response Curvementioning

confidence: 77%

Section: Nonmonotonic Dose Response Curvementioning

confidence: 94%

Section: Mathematical Description Of Receptor Bindingmentioning

confidence: 99%

Section: Mathematical Description Of Receptor Bindingmentioning

confidence: 99%

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Absolute Ligand Discrimination by Dimeric Signaling Receptors

Fathi

Nayak

Feld

et al. 2016

Biophysical Journal

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“…While unexpected on the basis of the ELISA experiments showing only moderate competition, together with the observation that receptor immobilization substantially changed the binding properties in SPR, this result may indicate that differences in the immobilization and/or surface properties may have significant impact on the receptor conformation and consequently binding of soluble IFN. In fact, interpreting the 50% binding level as a gross estimate of an empirical K D of the ELISA titrations with each individual IFN, the affinity of the receptor in the ELISA experiments is in the high nanomolar and low micromolar range, respectively, which is substantially higher than the SPR results indicate (and as compared estimates of affinity in the literature [14]). Therefore, we interpret the receptor state immobilized on the SPR surface more representative of the native state.…”

Section: Analysis Of Ifn-α2c and Cm3 Interaction With Ifnar2-ec By Sprmentioning

confidence: 85%

Two Interferons Alpha Influence Each Other during Their Interaction with the Extracellular Domain of Human Type Interferon Receptor Subunit 2

et al. 2007

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The interaction between two human interferons alpha (IFN-αs) and the extracellular (EC) domain of human type I IFN receptor subunit 2 (IFNAR2) was analyzed. Previous experiments using Daudi cells showed that IFN-α21b and some IFN-α hybrids (made from IFN-α2c and 21b) competed poorly for the IFN-α2b binding site. This study examined the causes of the poor competition between these IFN-αs. IFN-α2c and the IFN hybrid CM3 {IFN-α21b(1-75)(81-95)/IFN-α2c(76-80)(96-166), Y86K} were selected for this study based on their cell binding and biological properties. Competitive binding ELISA, native electrophoresis followed by Western blot, electrospray ionization mass spectrometry (ESI-MS), surface plasmon resonance biosensor (SPR) analysis, as well as neutralization of antiproliferative activities on Daudi cells in the presence of soluble IFNAR2-EC show evidence that each of the described IFN-α subtypes affected the binding of the other IFN-α to IFNAR2-EC by affecting the stability of the complex, i.e. dissociation of the complex. Moreover, native electrophoresis with different IFNAR2-EC mutants showed that IFN-α2c and CM3 utilize different amino acids in the binding domain of IFNAR2-EC. In addition to that, analytical ultracentrifugation (AUC) revealed differences in the oligomeric state of the two studied interferons. Our results demonstrated that two individual IFN-αs interact differentially with IFNAR2-EC and influence each other during this interaction. This study contributes to the understanding of the mutual interaction between multiple IFN-α subtypes during the competition for binding to the receptor.In mammals, the type I IFNs are grouped into five major classes: α, β, ε, κ, ω (1,2,3). They are induced in all nucleated cells in response to viral and bacterial infections, natural and synthetic double-stranded RNA, mitogens, protozoa and certain cytokines (3,4).Human IFN-α is represented by a group of related subtypes, encoded by a multigene family comprising 14 non-allelic genes. At the protein level, there is 75%-99% identity in the primary structure of human IFN-α species (5,6,7). Individual subtypes show quantitatively distinct spectra of antiviral, antiproliferative and immunomodulatory activities (8,9,10,11). The existence of the numerous subtypes of IFN-α may provide a fine mechanism of regulating the biological effect of IFN.

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Human pDCs display sex‐specific differences in type I interferon subtypes and interferon α/β receptor expression

et al. 2017

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The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-α, in response to toll-like receptor (TLR)7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex-specific differential expression of IFN-Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFN-α subtypes. In addition, pDCs from females had higher levels of IFN-β mRNA after stimulation, indicating that sex differences in IFN-I production by pDCs were mediated by a signaling event upstream of the first loop of IFN-I mRNA transcription. Furthermore, the surface expression levels of the common IFN-α/β receptor subunit 2 were significantly higher on pDCs from females in comparison to males. These data indicate that higher IFN-α production is already established at the mRNA level and propose a contribution of higher IFN-α/β receptor 2 expression on pDCs to the immunological differences in IFN-I production observed between females and males.

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Differential Receptor Subunit Affinities of Type I Interferons Govern Differential Signal Activation

Cited by 199 publications

References 44 publications

Absolute Ligand Discrimination by Dimeric Signaling Receptors

Absolute Ligand Discrimination by Dimeric Signaling Receptors

Two Interferons Alpha Influence Each Other during Their Interaction with the Extracellular Domain of Human Type Interferon Receptor Subunit 2

Human pDCs display sex‐specific differences in type I interferon subtypes and interferon α/β receptor expression

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