CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

Saggio, Isabella; Gloaguen, Isabelle; Poiana, Giancarlo; Laufer, Ralph

doi:10.1002/j.1460-2075.1995.tb07307.x

Cited by 54 publications

(56 citation statements)

References 45 publications

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“…In CNTF, Arg 25 and Arg 28 in helix A, Gln 63 and Trp 64 in the AB-loop, Gln 74 in helix B . and Gln 167 and Arg 177 in helix D Saggio et al, 1995) may form part of site I (CNTFR site); Lys 26 and Asp 30 in helix A (Inoue et al, 1995;Panayotatos et al, 1995;Thier et al, 1995;di Marc0 et al, 1996) @sandwich built up from one three-stranded &sheet packed against one four-stranded sheet. The CBD of the IL-6R is characteristic of the class I cytokine receptors (Bazan, 1990a(Bazan, , 1990b.…”

Section: Il-6: Structure-function Relationshipsmentioning

confidence: 99%

Interleukin‐6: Structure‐function relationships

et al. 1997

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Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

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Section: Il-6: Structure-function Relationshipsmentioning

confidence: 99%

Interleukin‐6: Structure‐function relationships

et al. 1997

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“…19,39 Second, the myelopoietin group A consensus sequence is identical to the parent sequence at 40, 44 and 49 ( Table 2), suggesting that the specific parental amino acid sequences at these positions may be optimal for activity in our hG-CSF proliferation assay, and that lack of myelopoietin variants with better agonist activity may not be related to a non-linear relationship between affinity/agonist activity. If other positions been mutagenized, myelopoietin variants with enhanced hG-CSF receptor agonist activity might have been identified.…”

Section: Discussionmentioning

confidence: 93%

“…Thus display-based maturation of receptor affinity is applicable to engineering some, 19,39 but not all, 34 protein hormones for enhanced activity. Also, affinity screening of peptide libraries on phage can identify novel peptidic agonists of cytokine receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Also, affinity screening of peptide libraries on phage can identify novel peptidic agonists of cytokine receptors. [38][39][40][41][42][43] Maturation of the affinity of a polypeptide for a receptor to enhance its potency is applicable if its agonist activity is limited by its affinity for that receptor. This can be assumed when screening a random peptide library, but it is not a priori obvious whether any given native protein hormone is so limited: the fact has to be determined empirically.…”

Section: Discussionmentioning

confidence: 99%

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Phage display mutagenesis of the chimeric dual cytokine receptor agonist myelopoietin

Ibdah²,

Valkenburgh

et al. 2001

Leukemia

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Myelopoietins comprise a class of chimeric cytokine receptor agonists consisting of an hIL-3 (human interleukin-3) receptor agonist and an hG-CSF (human granulocyte colony-stimulating factor) receptor agonist linked head-to-tail at their respective carboxy and amino termini. The combination of an early acting cytokine (hIL-3) with a late acting one (hG-CSF) allows efficient hematopoeitic reconstruction following myeloablative insult, and drives differentiation of non-myelocytic lineages (ie thrombocytic lineages) that are inaccessible using hG-CSF alone, in both preclinical models and clinical settings. A myelopoietin species was displayed and mutagenized on filamentous bacteriophage: both component agonists of myelopoietin were presented in biologically functional conformations as each recognized its corresponding receptor. Five amino acid positions in a short region of the hG-CSF receptor agonist module of myelopoietin that had been identified as important for proliferative activity were mutagenized. Display was used because it allows very 'deep' mutagenesis at selected residues: Ͼ10 5 substitution variants were affinity-screened using the hG-CSF receptor and 130 new, active variants of myelopoietin were identified and characterized. None of the selected variants were significantly more active than the parental myelopoietin species in a hG-CSF-dependent cell proliferation assay, though many were as active. Many of these relatively high-activity variants contained parental amino acids at several positions, suggesting the parental sequence may already be optimal at these positions for the assays used, and potentially accounting for the failure to identify enhanced bioactivity variants. Analysis of substitutions of high-activity variants complements and extends previous alanine scanning, and other genetic and biochemical data for hG-CSF variants. Leukemia (2001) 15, 1277-1285.

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“…First, the biological activity of CNTF is increased 30-fold when the cytokine signals through soluble CNTFR␣ as compared with the membrane-bound form of the receptor (61). In a similar manner, IL-6 combined with its soluble receptor enhances neuronal survival and neurite extension to a greater extent than IL-6 alone, despite the neuronal expression of IL-6 receptors (62).…”

Section: Discussionmentioning

confidence: 99%

Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

Ozog¹,

Modha

Church

et al. 2008

Journal of Biological Chemistry

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Attempts to promote neuronal survival and repair with ciliary neurotrophic factor (CNTF) have met with limited success. The variability of results obtained with CNTF may, in part, reflect the fact that some of the biological actions of the cytokine are mediated by a complex formed between CNTF and its specific receptor, CNTFR␣, which exists in both membrane-bound and soluble forms. In this study, we compared the actions of CNTF alone and CNTF complexed with soluble CNTFR␣ (hereafter termed "Complex") on neuronal survival and growth. Although CNTF alone produced limited effects, Complex protected against glutamate-mediated excitotoxicity via gap junction-dependent and -independent mechanisms. Further examination revealed that only Complex promoted neurite outgrowth. Differential gene expression analysis revealed that, compared with CNTF alone, Complex differentially regulates several neuroprotective and neurotrophic genes. Collectively, these findings indicate that CNTF exerts more robust effects on neuronal survival and growth when applied in combination with its soluble receptor.

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CNTF variants with increased biological potency and receptor selectivity define a functional site of receptor interaction.

Cited by 54 publications

References 45 publications

Interleukin‐6: Structure‐function relationships

Interleukin‐6: Structure‐function relationships

Phage display mutagenesis of the chimeric dual cytokine receptor agonist myelopoietin

Co-administration of Ciliary Neurotrophic Factor with Its Soluble Receptor Protects against Neuronal Death and Enhances Neurite Outgrowth

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