Shared receptor components but distinct complexes for α and β interferons 1 1Edited by M. Yaniv

Lewerenz, Malte; Mogensen, K. E.; Uzé, Gilles

doi:10.1006/jmbi.1998.2026

Cited by 76 publications

(76 citation statements)

References 55 publications

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“…IFN-␤ interacts with ifnar2 with a similar set of residues as IFN-␣2, but with very different ⌬⌬G values upon mutation (9,10). It is tempting to try to explain this difference by using the model generated here, assuming that IFN-␤ binds to the same epitope of ifnar2 as IFN-␣2.…”

Section: Discussionmentioning

confidence: 98%

“…Independent of these docking experiments, the interaction sites on IFN-␣2 and ifnar2 were probed by single mutagenesis (9)(10)(11)(12). The good agreement between the active sites as determined from single mutagenesis and the binding interface provides an experimental measure of the quality of the model (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Mutational studies have revealed the mutual binding sites on IFN-␣2 and ifnar2. On IFN-␣2, ifnar2 binds to the A helix (residues 12-15), the AB loop (residues [26][27][28][29][30][31][32][33][34][35], and the E helix (residues 144-153) (7), whereas on ifnar2, IFN-␣2 binds to three loops of the N-terminal domain of the receptor (residues 45-52, 75-82, and 102-106) with no significant binding detected toward the Cterminal domain (8)(9)(10). Determination of the receptor-ligand structure will significantly promote our understanding of IFN signaling at the molecular level.…”

mentioning

confidence: 99%

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Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Roisman

Piehler

Trosset

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The pleiotropic activity of type I interferons has been attributed to the specific interaction of IFN with the cell-surface receptor components ifnar1 and ifnar2. To date, the structure of IFN has been solved, but not that of the receptor or the complex. In this study, the structure of the IFN-␣2-ifnar2 complex was generated with a docking procedure, using nuclear Overhauser effect-like distance constraints obtained from double-mutant cycle experiments. The interaction free energy between 13 residues of the ligand and 11 of the receptor was measured by double-mutant cycles. Of the 100 pairwise interactions probed, five pairs of residues were found to interact. These five interactions were incorporated as distance constraints into the flexible docking program PRODOCK by using fixed and movable energy-gradient grids attached to the receptor and ligand, respectively. Multistart minimization and Monte Carlo minimization docking of IFN-␣2 onto ifnar2 converged to a welldefined average structure, with the five distance constraints being satisfied. Furthermore, no structural artifacts or intraloop energy strain were observed. The mutual binding sites on IFN-␣2 and ifnar2 predicted from the model showed an almost complete superposition with the ones determined from mutagenesis studies. Based on this structure, differences in IFN-␣2 versus IFN-␤ binding are discussed.protein-protein interaction ͉ PRODOCK ͉ Monte Carlo minimization ͉ grids T ype I interferons (IFNs) are a family of homologous cytokines that potently elicit an antiviral and antiproliferative state in cells. All human type I IFNs (IFN-␣, -␤, and -) bind to a cell surface receptor consisting of two transmembrane proteins, type I IFN receptor (ifnar) 1 (1) and ifnar2 (2), which associate upon binding. IFN binds with high affinity to ifnar2, probably recruiting ifnar1 subsequently. Type I IFNs belong to the class of helical cytokines and are built of five helices. The structures of human IFN-␣2 (3) and IFN-␤ have been resolved (4). The receptor structures are unknown, but can be modeled by homology to human cytokine receptors with known structures such as tissue factor (5) and IFN-␥ receptor (6). Mutational studies have revealed the mutual binding sites on IFN-␣2 and ifnar2. On IFN-␣2, ifnar2 binds to the A helix (residues 12-15), the AB loop (residues 26-35), and the E helix (residues 144-153) (7), whereas on ifnar2, IFN-␣2 binds to three loops of the N-terminal domain of the receptor (residues 45-52, 75-82, and 102-106) with no significant binding detected toward the Cterminal domain (8-10). Determination of the receptor-ligand structure will significantly promote our understanding of IFN signaling at the molecular level.Docking of protein complexes, and calculating the conformational changes that occur at the binding interface, is a computational challenge. Rigid protein docking software algorithms are fast and can be used to dock two proteins for which the NMR or x-ray structures have been solved independently (11, 12). However, successful docking relies o...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Roisman

Piehler

Trosset

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, co-immunoprecipitation of IFNaR1 and IFNaR2-2 can be achieved upon IFN␤ but not IFN␣ treatment (24,25), and two monoclonal antibodies or a polyclonal antiserum, directed against IFNaR1, block the activity of IFN␣ but not that of IFN␤ (26,27). In addition, mutagenesis studies of the IFNaR2-2 chain showed differential receptor activation since (i) intracellular deletions abrogated only the IFN␤ and not the IFN␣-induced antiviral response, while activation of the JAK/Stat pathway was equal in both cases (28), and (ii) extracellular mutations created receptor complexes that showed preferential binding for each of the ligands (27). It is also possible to obtain mutations in IFN␤ that mimic IFN␣ activity (29).…”

mentioning

confidence: 99%

“…High affinity ligand binding and activation of the IFN␣/␤ signaling pathways requires clustering of the IFNaR1 with the IFNaR2-2 chain (4,5,7,30,31), but it has been postulated that IFN␤ may also be capable of clustering the IFNaR2-2 subunit alone (27).…”

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confidence: 99%

Dimerization of the Interferon Type I Receptor IFNaR2–2 Is Sufficient for Induction of Interferon Effector Genes but Not for Full Antiviral Activity

Pattyn¹,

Ostade²,

Schauvliege³

et al. 1999

Journal of Biological Chemistry

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We constructed chimeric receptors wherein the extracellular domain of the erythropoietin receptor (EpoR) was fused to the transmembrane and intracellular domains of the interferon (IFN) type I receptor subunits, IFNaR1 or IFNaR2-2. Transfection into 2fTGH and Tyk2-deficient 11,1 cells showed that EpoR/IFNaR2-2 alone was able to transduce a signal upon stimulation with erythropoietin (Epo), as judged by induction of the interferon type I-inducible 6-16 promoter. In contrast, protection against infection with encephalomyocarditis virus or vesicular stomatitis virus was reduced or absent, respectively. To further investigate the role of IFNaR1 in the induction of an antiviral state, we analyzed the Epo-versus IFN␣-induced transcription of a set of genes, involved in antiviral protection. Up to 24 h after stimulation with Epo or IFN␣, comparable transcription of the p56, dsRNA-dependent protein kinase, 2-5A synthetase, and MxA genes was seen. However, at later time points, only in the case of Epo induction, a sharp decrease of mRNA levels was observed. Western blotting analysis of dsRNA-dependent protein kinase showed a similar pattern at the protein level. Taken together, our results imply a role for IFNaR1 in the induction of sustained mRNA and protein levels that are likely required for optimal antiviral activity.It is generally accepted that activation of a cell by a cytokine is initiated by ligand-induced clustering of receptor subunits, which can occur as di-, tri-, or higher order oligomers, involving identical or related subunits. With the exception of the heptamembrane-spanning receptors, members from the hematopoietin/IFN, 1 tumor necrosis factor/nerve growth factor, and tyrosine kinase receptor families are all activated by this mechanism of cytokine-driven multimerization. Ligand binding to the first receptor component induces the association with additional receptor subunits eventually resulting in an increase of affinity for the ligand (1, 2). Alternatively, preformed receptor complexes may also exist on the cell membrane (3). Interferons belong to the class I cytokine family and are divided into type I interferons (at least 14 IFN␣ subtypes, IFN␤, IFN, and the bovine embryonic IFN) that have antiviral, cytostatic, and hematopoietic activities on many cell types, and the type II interferon or IFN␥ that is also involved in many immune functions. Both types of interferons bind to distinct receptors that belong to the class I cytokine receptors. The interferon type I receptor (IFNaR) is composed of two subunits, IFNaR1 and IFNaR2-2. As a result of alternative splicing, subtypes of the latter subunit do also exist: a cytoplasmic truncated transmembrane form (IFNaR2-1) and a soluble form (IFNaR2-3) (4 -8).A large body of evidence has shown that the class I cytokine receptors make use of associated kinases (JAKs) to start intracellular tyrosine phosphorylation, resulting in the activation of the so-called Stat proteins. This JAK/Stat pathway is essential for transcription of many of the cytokine-inducible ge...

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Standing on Shoulders: Interferon Research From Viral Interference to Lupus Pathogenesis and Treatment

Crow,

Olferiev,

Kirou

2024

Arthritis & Rheumatology

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The discovery of interferon in the 1950s represents much more than the identification of the first cytokine and the key mediator of anti‐viral host defense. Defining the molecular nature and complexity of the type I interferon family, as well as its inducers and molecular mechanisms of action, was the work of investigators working at the highest level and producing insights of great consequence. Current knowledge of receptor‐ligand interactions, cell signaling, and transcriptional regulation derive from studies of type I interferon. It is on the shoulders of the giants who produced that knowledge that others stand and have revealed critical mechanisms of the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. The design of novel therapeutics is informed by the advances in investigation of type I interferon, with the potential for important impact on patient management.

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Shared receptor components but distinct complexes for α and β interferons 1 1Edited by M. Yaniv

Cited by 76 publications

References 55 publications

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking

Dimerization of the Interferon Type I Receptor IFNaR2–2 Is Sufficient for Induction of Interferon Effector Genes but Not for Full Antiviral Activity

Standing on Shoulders: Interferon Research From Viral Interference to Lupus Pathogenesis and Treatment

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