상세 정보

underline
Metadata Downloads : dc(xml) or Excel
Cited 0 time in scopus ci

Title 

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

Authors 

Soo Hyun KimTania AzamDaniela NovickDo Young YoonLeonid L ReznikovPhilip BurflerMenachem RubinsteinCharles A Dinarello

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2002

Citation 

Journal of Biological Chemistry, vol. 277, no. 13, pp. 10998-11003

Keywords 

amino acidsamino acidglutamic acidinterleukin 18amino acid sequencehumanhuman cellnonhumaninterleukin-18sequence homology, amino acid

Abstract 

Interleukin-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.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M108311200

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


There are no files associated with this item.
qrcode

FusionCharts.
DSpace Software Coptright(c) 2010 MIT and Hewleft-Packard  /  KRIBB-REPOSITORY ( Email:jakim@kribb.re.kr)