Identification of amino acid residues critical for biological activity in human interleukin-18

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dc.contributor.authorSoo Hyun Kim-
dc.contributor.authorTania Azam-
dc.contributor.authorDaniela Novick-
dc.contributor.authorDo Young Yoon-
dc.contributor.authorLeonid L Reznikov-
dc.contributor.authorPhilip Burfler-
dc.contributor.authorMenachem Rubinstein-
dc.contributor.authorCharles A Dinarello-
dc.date.accessioned2017-04-19T08:58:58Z-
dc.date.available2017-04-19T08:58:58Z-
dc.date.issued2002-
dc.identifier.issn0021-9258-
dc.identifier.uri10.1074/jbc.M108311200ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/5805-
dc.description.abstractInterleukin-18 (IL-18) is a pro-inflammatory cytokine, and IL-18-binding protein (IL-18BP) is a naturally occurring protein that binds IL-18 and neutralizes its biological activities. Computer modeling of human IL-18 identified two charged residues, Glu-42 and Lys-89, which interact with oppositely charged amino acid residues buried in a large hydrophobic pocket of IL-18BP. The cell surface IL-18 receptor a chain competes with IL-18BP for IL-18 binding, although the IL-18 receptor α chain does not share significant homology to IL-18BP. In the present study, Glu-42 was mutated to Lys and Lys-89 to Glu; Glu-42 and Lys-89 were also deleted separately. The deletion mutants (E42X and K89X) were devoid of biological activity, and the K89E mutant lost 95% of its activity. In contrast, compared with wild-type (WT) IL-18, the E42K mutant exhibited a 2-fold increase in biological activity and required a 4-fold greater concentration of IL-18BP for neutralization. The binding of WT IL-18 and its various mutants to human natural killer cells was evaluated by competition assays. The mutant E42K was more effective than WT IL-18 in inhibiting the binding of 125I-IL-18 to natural killer cells, whereas the three inactive mutants E42X, K89E, and K89X were unable to compete with 125I-IL-18 for binding. Similarly, WT IL-18 and the E42K mutant induced degradation of Iκ-Bα, whereas the three biologically inactive mutants did not induce degradation. The present study reveals that Glu-42 and Lys-89 are critical amino acid residues for the integrity of IL-18 structure and are important for binding to cell surface receptors, for signal transduction, and for neutralization by IL-18BP.-
dc.publisherElsevier-
dc.titleIdentification of amino acid residues critical for biological activity in human interleukin-18-
dc.title.alternativeIdentification of amino acid residues critical for biological activity in human interleukin-18-
dc.typeArticle-
dc.citation.titleJournal of Biological Chemistry-
dc.citation.number13-
dc.citation.endPage11003-
dc.citation.startPage10998-
dc.citation.volume277-
dc.contributor.affiliatedAuthorDo Young Yoon-
dc.contributor.alternativeName김수현-
dc.contributor.alternativeNameAzam-
dc.contributor.alternativeNameNovick-
dc.contributor.alternativeName윤도영-
dc.contributor.alternativeNameReznikov-
dc.contributor.alternativeNameBurfler-
dc.contributor.alternativeNameRubinstein-
dc.contributor.alternativeNameDinarello-
dc.identifier.bibliographicCitationJournal of Biological Chemistry, vol. 277, no. 13, pp. 10998-11003-
dc.identifier.doi10.1074/jbc.M108311200-
dc.description.journalClassY-
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