The amino-terminal helix of GM-CSF and IL-5 governs high affinity binding to their receptors.

Shanafelt, Armen B.; Miyajima, Atsushi; Kitamura, Toshio; Kastelein, Robert A.

doi:10.1002/j.1460-2075.1991.tb04987.x

Cited by 100 publications

(52 citation statements)

References 35 publications

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“…IL-10 is predicted to be in the four a-helix bundle cytokine family (37), and most CRs for these cytokines (for example, IL-2-IL-7 and granulocyte and granulocyte/macrophage colony-stimulating factors) are in the class I group of the CR superfamily (31). However, mIL-lOR lacks the two distinctive sequence motifs of four conserved cysteines (paired sequentially), a tryptophan in the N-terminal portion (C-Xo20-C-X-W-X22 -C-X8s.5-C, where X is any amino acid), and a nearly invariant "WSXWS" box near the C terminus of the extracellular binding domains of class I CRs (31,38).…”

Section: Resultsmentioning

confidence: 99%

A receptor for interleukin 10 is related to interferon receptors.

Liu

Khan

et al. 1993

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

219

138

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We isolated cDNAs encoding a mouse interleukin 10 receptor (mIL-10R) from mouse mast cell and macrophage cell lines. The two cDNAs are substantially identical and express an approximately 110-kDa polypeptide in COS7 cells, which binds mIL-10 specifically. A mouse pro-B-cell line (Ba/F3) expressing transfected recombinant mIL-10R binds IL-10 with high affinity (approximately 70 pM) and proliferates in response to mIL-10. mIL-10R is structurally related to interferon receptors (IFNRs). Since IL-10 inhibits macrophage activation by IFN-gamma, a possible implication of this relationship interaction of IL-10R and IFN-gamma R or their signaling pathways.

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Section: Resultsmentioning

confidence: 99%

A receptor for interleukin 10 is related to interferon receptors.

Liu

Khan

et al. 1993

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

219

138

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“…Neutralizing monoclonal antibodies have also been demonstrated to bind to the region incorporating part of the putative helix A of hIL-6 (Brakenhoff et al, 1990). By analogy to other receptor systems, the corresponding region of GM-CSF was shown to be principally involved in binding to the &subunit of the GM-CSF receptor (Shanafelt et al, 1991). It was noted by these authors that, when aligned with other cytokines, an acidic residue (Glu-37 in mIL-6) was conserved in all cytokines belonging to this four-a-helical bundle family, thereby implying the importance of this acidic residue in receptor binding.…”

Section: Discussionmentioning

confidence: 96%

Effect of pH and denaturants on the folding and stability of murine interleukin‐6

et al. 1993

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The conformation and stability of a recombinant mouse interleukin-6 (mlL-6) has been investigated by analytical ultracentrifugation, fluorescence spectroscopy, urea-gradient gel electrophoresis, and near-and far-ultraviolet circular dichroism. On decreasing the pH from 8.0 to 4.0, the tryptophan fluorescence of mIL-6 was quenched 40%, the midpoint of the transition occurring at pH 6.9. The change in fluorescence quantum yield was not due to unfolding of the molecule because the conformation of mIL-6, as judged by both urea-gradient gel electrophoresis and CD spectroscopy, was stable over the pH range 2.0-10.0. Sedimentation equilibrium experiments indicated that mIL-6 was monomeric, with a molecular mass of 22,500 Da over the pH range used in these physicochemical studies. Quenching of tryptophan fluorescence (20%) also occurred in the presence of 6 M guanidine hydrochloride upon going from pH 7.4 to 4.0 suggesting that an amino acid residue vicinal in the primary structure to one or both of the two tryptophan residues, Trp-36 and Trp-160, may be partially involved in the quenching of endogenous fluorescence. In this regard, similar results were obtained for a 17-residue synthetic peptide, peptide H1, which corresponds to an N-terminal region of mIL-6 (residues Val-27-Lys-43). The pH-dependent acid quenching of endogenous tryptophan fluorescence of peptide H1 was 30% in the random coil conformation and 60% in the presence of a-helix-promoting solvents. Replacement of His-33 with Ala-33 in peptide HI alleviated a significant portion of the pH-dependent quenching of fluorescence suggesting that the interaction of the imidazole ring of His-33 with the indole ring of Trp-36 is a major determinant responsible for the quenching of the endogenous protein fluorescence of mIL-6. Keywords: circular dichroism; denaturation; fluorescence studies; interleukin-6; protein structure Interleukin-6 is a multifunctional cytokine that acts on a wide variety of tissues to elicit a broad spectrum of biological functions including terminal differentiation of B cells, growth and differentiation of T cells, and regulation of the acute-phase responses. IL-6 is also capable of inducing the differentiation of hematopoietic progenitor cells and megakaryocytes (for reviews see Kishimoto [1989], Van Snick [19901, and Gordon& Hoffman [1992]). Abbreviutions: IL-6, interleukin-6; m-, murine; h-, human; GdnHC1, guanidine hydrochloride; SDS, sodium dodecyl sulfate; MES, 2-(N-morpho1ino)ethane sulfonic acid; S, weight average sedimentation coefficient; [ B ] M~~, mean residue ellipticity; HEPES, N-2-hydroxyethylpiperazine-N1-2-ethane sulfonic acid; Tris, Tris(hydroxymethy1)aminomethane; CAPS, 3-(cyclohexylamino)-I-propane sulfonic acid; TFE, trifluoroethanol; GM-CSF, granulocyte-macrophage colony-stimulating factor.

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“…Like the common 0-chain receptor for IL-3, IL-5, and GM-CSF, the D200' domain is located near the transmembrane region of the receptor. Finally, the common / 3 chain interacts with residues in helices A and C at site 2 of these cytokines based on studies of the binding interactions of mutated cytokines (GM-CSF, 1L-3, and IL-5) and their respective receptors (Shanafelt et al, 1991;Lopez et al, 1992aLopez et al, , 1992bKastelein & Shanafelt, 1993;Woodcock et al, 1994). Residues in helices A and C of HuIFNa8 interact with receptor residues in the HuIFNa8-IFNAR site 2 model.…”

Section: Mh Seto Et Atmentioning

confidence: 99%

Homology model of human interferon‐α8 and its receptor complex

Seto¹,

Harkins²,

Adler³

et al. 1995

Protein Science

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Human interferond (HuIFNa8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic superfamily that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor-like domains (D200 and D200'), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFNa8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which H G H receptor is a member. The cytokine receptor-like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X-ray structure. Models of the complexes of HuIFNa8 with the receptor subunits were built by superpositioning the conserved C a backbone of the HuIFNa8 and receptor subunit models with HGH and its receptor complex. The HuIFNa8 model was constructed from the Ca coordinates of murine interferon-p crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFNa8 interacting with p40 at site 1 and the D200' domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFNa8 correspond to functionally important residues determined previously for human IFNal, IFNa2, and IFNa4 subtypes by site-directed mutagenesis studies. The models predict regions of interaction between HuIFNa8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN-a subtypes and IFN-p) and their respective receptor components.

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The amino-terminal helix of GM-CSF and IL-5 governs high affinity binding to their receptors.

Cited by 100 publications

References 35 publications

A receptor for interleukin 10 is related to interferon receptors.

A receptor for interleukin 10 is related to interferon receptors.

Effect of pH and denaturants on the folding and stability of murine interleukin‐6

Homology model of human interferon‐α8 and its receptor complex

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