The interleukin-2 and interleukin-4 receptors studied by molecular modelling

Bamborough, Paul; Hedgecock, Charles J. R.; Richards, William G.

doi:10.1016/s0969-2126(94)00085-9

Cited by 55 publications

(52 citation statements)

References 59 publications

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“…This is in aggreement with a mutational analysis indicating that IL-4 has one binding site for each of these receptor proteins (Kruse et al, 1993;Muller et al, 1994). The heterotrimeric complex consisting of the extracellular domains of the receptor a and yc chains (Bamborough et al, 1994; and of 1L-4 has been modelled on the basis of the crystal structure of human growth hormone/growth hormone receptor complex (de Vos et al, 1992) employing the three-dimensional structure of IL-4 (Smith et al, 1992;Wlodawer et al, 1992;Walter et al, 1992;Powers et al, 1992) as well as the information on functional amino acid side chains in IL-4 (Kruse et al, 1992(Kruse et al, , 1993.…”

supporting

confidence: 71%

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Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction

Shen

Hage

Sebald

1996

European Journal of Biochemistry

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An engineered interleukin-4-binding protein (IL4-BP) representing the extracellular domain of the human interleukin-4 (IL-4) receptor a chain was expressed in Sf9 cells. The purified IL4-BP was immobilized via a single biotinylated SH group near the carboxyl end to a biosensor matrix and analysed in real time for interaction with IL-4 and IL-4 variants. IL-4 was bound to IL4-BP at a molar ratio of approximately 1 : l . The association and dissociation at pH 7.4 and 150 mM NaCl had rate constants of 1.9 2 0.3 X 10' M-' s-I and 2 ? 1 X lo-' s-', respectively. Glycosylation and engineered amino acid substitutions of IL4-BP did not alter the kinetic constants as shown by a parallel analysis of IL4-BP variants produced in Eschevichia coli or Chinese hamster ovary cells. The rate of association was only slighly affected in binding-deficient variants [E9Q]IL-4 and [R88Q]IL-4 and by acidic pH down to values of 4.5, but it was reduced up to fivefold at higher ionic strength. The rate of dissociation was increased 70-fold and 150-fold with the 1L-4 variants and fivefold at an acidic pH of 4.5, but it was not affected by high ionic strength. Temperatures between 6°C and 37°C yielded similar rates of IL-4 dissociation and only a marginally reduced rate of IL-4 association at 6°C.These results indicate that the high-affinity binding of IL-4 to its receptor (Kd=lOO pM) is mainly the result of an unusually high association rate. The IL-4/IL4-BP interaction appears to be dominated by charge effects. The exceedingly high rate of IL-4IIU-BP association is augmented by the overall electrostatic potentials of both proteins (electrostatic steering). Localized charges and the formation of ion pairs may control the rate of complex dissociation.

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supporting

confidence: 71%

“…(Bazan, 1990). According to model building (Bamborough et al, 1994; these residues could form three disulfide bonds. The seventh cysteine at position 182 was substituted by an alanine, and a new cysteine was introduced in place of Glu206.…”

Section: Il4-bp Variantsmentioning

confidence: 99%

Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction

Shen

Hage

Sebald

1996

European Journal of Biochemistry

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“…Peptides related to erythropoietin (36) and thrombopoietin (37) have been selected by random phage display, whereas p1-30 corresponds to the natural ␣ helix A sequence of IL-2. Experimental data supporting an IL-2/IL-2R model where ␣ helix A of IL-2 is involved in binding to IL-2R␤ have been published (26,38). This is consistent with the unique properties of p1-30, which behaves as a selective agonist of IL-2R␤.…”

Section: Discussionsupporting

confidence: 69%

IL-2Rβ Agonist P1–30 Acts in Synergy with IL-2, IL-4, IL-9, and IL-15: Biological and Molecular Effects

Eckenberg

Moreau

Melnyk

et al. 2000

The Journal of Immunology

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From the sequence of human IL-2 we have recently characterized a peptide (p1–30), which is the first IL-2 mimetic described. P1–30 covers the entire α helix A of IL-2 and spontaneously folds into a α helical homotetramer mimicking the quaternary structure of a hemopoietin. This neocytokine interacts with a previously undescribed dimeric form of the human IL-2 receptor β-chain likely to form the p1–30 receptor (p1–30R). P1–30 acts as a specific IL-2Rβ agonist, selectively inducing activation of CD8 and NK lymphocytes. From human PBMC we have also shown that p1–30 induces the activation of lymphokine-activated killer cells and the production of IFN-γ. Here we demonstrate the ability of p1–30 to act in synergy with IL-2, -4, -9, and -15. These synergistic effects were analyzed at the functional level by using TS1β, a murine T cell line endogenously expressing the common cytokine γ gene and transfected with the human IL-2Rβ gene. At the receptor level, we show that expression of human IL-2Rβ is absolutely required to obtain synergistic effects, whereas IL-2Rα specifically impedes the synergistic effects obtained with IL-2. The results suggest that overexpression of IL-2Rα inhibits p1–30R formation in the presence of IL-2. Finally, concerning the molecular effects, although p1–30 alone induces the antiapoptotic molecule bcl-2, we show that it does not influence mRNA expression of c-myc, c-jun, and c-fos oncogenes. In contrast, p1–30 enhances IL-2-driven expression of these oncogenes. Our data suggest that p1–30R (IL-2Rβ)2 and intermediate affinity IL-2R (IL-2Rβγ), when simultaneously expressed at the cell surface, may induce complementary signal transduction pathways and act in synergy.

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“…In fact, the most recent structural model of ␥c (16) predicted the formation of such an intrachain disulfide bond, based on an improved sequence alignment between human ␥c (h␥c) and GHR. Alternatively, we cannot rule out a direct participation of either of these cysteines in ligand binding because other models predicted interactions between cytokine residues and backbone atoms of Cys-160 in the h␥c (14,15).…”

Section: Discussionmentioning

confidence: 99%

Three Loops of the Common γ Chain Ectodomain Required for the Binding of Interleukin-2 and Interleukin-7

Olosz

Malek

2000

Journal of Biological Chemistry

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The common ␥ chain (␥c), a subunit of the interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 receptors, contributes to both cytokine binding and subsequent signal transduction. Using a model-based site-directed mutagenesis strategy, we have identified residues of the mouse ␥c extracellular domain that are required for normal ␥c-dependent enhancement of IL-2 and IL-7 binding. One of these sites, Tyr-103, is homologous to key ligand-interacting residues in the growth hormone and erythropoietin receptors, whereas Cys-161, Cys-210, and Gly-211 may function indirectly by maintaining the functional conformation of ␥c via formation of an intramolecular disulfide bond. These two cysteines are also required for the integrity of a putative epitope recognized by TUGm2, an antagonistic monoclonal antibody that blocks ␥c-dependent cytokine binding and bioactivity. These results are consistent with the involvement of three predicted loops in ␥c that contribute to the binding of both IL-2 and IL-7. Mutations in these loops have also been noted in the ␥c gene of patients with X-linked severe combined immunodeficiency.The common ␥ chain (␥c) 1 is a member of the type I cytokine receptor superfamily and functions as a shared subunit of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (reviewed in Refs. 1 and 2). In each of these receptors ␥c regulates signaling via the JAK3 tyrosine kinase associated with its cytoplasmic tail. The biological importance of ␥c is most dramatically illustrated by the fact that mutations of either ␥c or JAK3 are the primary causes of human X-linked severe combined immunodeficiency (X-SCID), characterized by a failure in T and natural killer cell development (3). Although ␥c does not detectably bind cytokines by itself, its recruitment into the IL-2, IL-4, and IL-7 receptor complexes enhances ligand binding. This is most evident in the context of the IL-2 receptor (IL-2R) where ␤␥ heterodimers bind IL-2 with 100-fold higher affinity than IL-2R␤ (4), and the affinity of ␣␤␥ trimers is 10-fold increased over ␣␤ complexes (5). A similar but more modest 3-5-fold increase in affinity has also been observed in the IL-4R (6) and IL-7R (7).Cytokines binding to type I cytokine receptors are typically folded as bundles of four ␣-helices. The receptor subunits, including ␥c, are characterized by extracellular homology regions composed of two fibronectin type III domains that are each composed of seven ␤-strands. The first domain contains four highly conserved cysteine residues linked by disulfide bonds whereas the second domain contains a highly conserved WSXWS motif (8). The prototypical members of the type I cytokine receptor superfamily are the growth hormone and erythropoietin receptors (EPORs) for which the crystal structure has been determined for the extracellular portion of the receptors together with their ligands (9, 10). The structure of the growth hormone receptor (GHR) complex (9) has been used as a template for homology modeling of a number of receptors within the family. Subsequent use of such m...

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The interleukin-2 and interleukin-4 receptors studied by molecular modelling

Cited by 55 publications

References 59 publications

Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction

Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction

IL-2Rβ Agonist P1–30 Acts in Synergy with IL-2, IL-4, IL-9, and IL-15: Biological and Molecular Effects

Three Loops of the Common γ Chain Ectodomain Required for the Binding of Interleukin-2 and Interleukin-7

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