Evidence for multiple binding sites for several components of human lymphoblastoid interferon-alpha

Hu, Renqiu; Gan, Yuxiang; Liu, Jilan; Miller, Dorothea M.; Zoon, Kathryn C.

doi:10.1016/s0021-9258(18)31429-7

Cited by 55 publications

(7 citation statements)

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“…It has been reported, for example, that IFN “consensus” has a higher affinity for the IFN receptor than IFN-α2 or IFN-α8 (), and several studies have shown that the antiviral activity of IFN-cons is higher than that of IFN-α2 or IFN-α8 ( , ). Moreover, Hu et al ( , ) ranked various IFN-α subtypes in terms of antiproliferative activity. The interaction of IFN-α8 and IFN-β with the human type I IFN receptors was evaluated from the distribution of their electrostatic potentials and an analysis of the binding surfaces on IFN-α2 for human IFNAR1 and IFNAR2.…”

Section: Discussionmentioning

confidence: 99%

Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity

et al. 2004

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The antiviral and antiproliferative activities of human type I interferons (IFNs) are mediated by two transmembrane receptor subunits, IFNAR1 and IFNAR2. To elucidate the role of IFNAR1 in IFN binding and the establishment of biological activity, specific residues of IFNAR1 were mutated. Residues (62)FSSLKLNVY(70) of the S5-S6 loop of the N-terminal subdomain of IFNAR1 and tryptophan-129 of the second subdomain of IFNAR1 were shown to be crucial for IFN-alpha binding and signaling and establishment of biological activity. Mutagenesis of peptide (278)LRV in the third subdomain shows that these residues are critical for IFN-alpha-induced biological activity but not for ligand binding. These data, together with the sequence homology of IFNAR1 with cytokine receptors of known structure and the recently resolved NMR structure of IFNAR2, led to the establishment of a three-dimensional model of the human IFN-alpha/IFNAR1/IFNAR2 complex. This model predicts that following binding of IFN to IFNAR1 and IFNAR2 the receptor complex assumes a "closed form", in which the N-terminal domain of IFNAR1 acts as a lid, resulting in the activation of intracellular kinases. Differences in the primary sequence of individual IFN-alpha subtypes and resulting differences in binding affinity, duration of ligand/receptor association, or both would explain differences in intracellular signal intensities and biological activity observed for individual IFN-alpha subtypes.

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Section: Discussionmentioning

confidence: 99%

Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity

et al. 2004

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“…Few studies have investigated the bioactivities of the various IFNα subtypes in a comprehensive manner (Lavoie et al, 2011), and it has been posited that the clinical utility of IFNα has been restricted by a lack of understanding of the differences between the subtypes (Gibbert et al, 2013). Although recombinant cytokines and engineered variants have been instrumental in revealing key differences in binding and bioactivity (Hu et al, 1993;Blatt et al, 1996;Brideau-Andersen et al, 2007;Kalie et al, 2007), a panel of recombinant antibodies with validated subtype specificities could provide a means of assessing IFNα subtype levels and activities in biological samples. For diseases in which type I IFNs are known to play a role (Hooks et al, 1979;Banchereau and Pascual, 2006;Higgs et al, 2011;Crow, 2014), such as rheumatoid arthritis and systemic lupus erythematosus, these tools could provide insight in to disease pathoetiology and potential therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is known that the various IFNα subtypes exhibit cell- (Hiscott et al, 1984;Nyman et al, 1998;Easlick et al, 2010) and ligand-dependent expression patterns (Hillyer et al, 2012), widely varying potencies (Moll et al, 2011), and potentially divergent activities (Ortaldo et al, 1984;Hu et al, 1993;Langer, 2007), a detailed understanding of their individual roles in the pathology of disease is lacking. Recent studies highlight this void by confirming the role of IFNα in a variety of autoimmune disorders (Burman et al, 1985;Imagawa et al, 1995;Atkinson and Eisenbarth, 2001;Blanco et al, 2001;Nestle et al, 2005;Li et al, 2008;Baccala et al, 2012;Asgari et al, 2013;Ferreira et al, 2014), and suggesting that individual subtypes potentially play a role in the development of human disease (Hirankarn et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

A panel of synthetic antibodies that selectively recognize and antagonize members of the interferon alpha family

Miersch

Kuruganti

Walter

et al. 2017

Protein Engineering, Design and Selection

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The 12 distinct subtypes that comprise the interferon alpha (IFNα) family of cytokines possess anti-viral, anti-proliferative and immunomodulatory activities. They are implicated in the etiology and progression of many diseases, and also used as therapeutic agents for viral and oncologic disorders. However, a deeper understanding of their role in disease is limited by a lack of tools to evaluate single subtypes at the protein level. Antibodies that selectively inhibit single IFNα subtypes could enable interrogation of each protein in biological samples and could be used for characterization and treatment of disease. Using phage-displayed synthetic antibody libraries, we have conducted selections against 12 human IFNα subtypes to explore our ability to obtain fine-specificity antibodies that recognize and antagonize the biological signals induced by a single IFNα subtype. For the first time, we have isolated antibodies that specifically recognize individual IFNα subtypes (IFNα2a/b, IFNα6, IFNα8b and IFNα16) with high affinity that antagonize signaling. Our results show that highly specific antibodies capable of distinguishing between closely related cytokines can be isolated from synthetic libraries and can be used to characterize cytokine abundance and function.

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“…Our previous results showed that hybrid IFNs with N-terminal portion derived from IFN-α21b competed poorly with IFN-α2b for cellular binding ( , ). CM3 is one of these hybrids, and also has a mutation in helix C (Y86K).…”

Section: Discussionmentioning

confidence: 99%

“…The type I IFNs bind with distinct affinities to the common type I IFN receptor complex (IFNAR), expressed on the surface of target cells in low numbers (100−5000 molecules/cell) ( − ). Functional human IFNAR is a heterodimeric complex composed of two transmembrane polypeptide chains, IFNAR1 and IRNAR2, with distinct complementary functions, which associate to form a heterodimer upon IFN-binding ( , ).…”

mentioning

confidence: 99%

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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Evidence for multiple binding sites for several components of human lymphoblastoid interferon-alpha

Cited by 55 publications

References 0 publications

Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity

Identification of Residues of the IFNAR1 Chain of the Type I Human Interferon Receptor Critical for Ligand Binding and Biological Activity

A panel of synthetic antibodies that selectively recognize and antagonize members of the interferon alpha family

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

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