Identification of amino acid residues critical for biological activity in human interleukin-18 - PubMed (original) (raw)
. 2002 Mar 29;277(13):10998-1003.
doi: 10.1074/jbc.M108311200. Epub 2002 Jan 14.
Affiliations
- PMID: 11790772
- DOI: 10.1074/jbc.M108311200
Free article
Identification of amino acid residues critical for biological activity in human interleukin-18
Soo-Hyun Kim et al. J Biol Chem. 2002.
Free article
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 alpha chain competes with IL-18BP for IL-18 binding, although the IL-18 receptor alpha 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 (125)I-IL-18 to natural killer cells, whereas the three inactive mutants E42X, K89E, and K89X were unable to compete with (125)I-IL-18 for binding. Similarly, WT IL-18 and the E42K mutant induced degradation of Ikappa-Balpha, 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.
Similar articles
- A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity.
Bufler P, Azam T, Gamboni-Robertson F, Reznikov LL, Kumar S, Dinarello CA, Kim SH. Bufler P, et al. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13723-8. doi: 10.1073/pnas.212519099. Proc Natl Acad Sci U S A. 2002. PMID: 12381835 Free PMC article. - Site-specific mutations in the mature form of human IL-18 with enhanced biological activity and decreased neutralization by IL-18 binding protein.
Kim SH, Azam T, Yoon DY, Reznikov LL, Novick D, Rubinstein M, Dinarello CA. Kim SH, et al. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3304-9. doi: 10.1073/pnas.051634098. Proc Natl Acad Sci U S A. 2001. PMID: 11248074 Free PMC article. - Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
Krumm B, Meng X, Li Y, Xiang Y, Deng J. Krumm B, et al. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20711-5. doi: 10.1073/pnas.0809086106. Epub 2008 Dec 22. Proc Natl Acad Sci U S A. 2008. PMID: 19104048 Free PMC article. - Interleukin 18 and interleukin 18 binding protein: possible role in immunosuppression of chronic renal failure.
Dinarello CA, Novick D, Rubinstein M, Lonnemann G. Dinarello CA, et al. Blood Purif. 2003;21(3):258-70. doi: 10.1159/000070699. Blood Purif. 2003. PMID: 12784053 Review. - Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection.
Hiscott J, Beauparlant P, Crepieux P, DeLuca C, Kwon H, Lin R, Petropoulos L. Hiscott J, et al. J Leukoc Biol. 1997 Jul;62(1):82-92. doi: 10.1002/jlb.62.1.82. J Leukoc Biol. 1997. PMID: 9225998 Review.
Cited by
- Inflammatory Mediators of Endothelial Dysfunction.
Dri E, Lampas E, Lazaros G, Lazarou E, Theofilis P, Tsioufis C, Tousoulis D. Dri E, et al. Life (Basel). 2023 Jun 20;13(6):1420. doi: 10.3390/life13061420. Life (Basel). 2023. PMID: 37374202 Free PMC article. Review. - Effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, with a focus on atherosclerosis.
Yang L, Zhang X, Wang Q. Yang L, et al. Front Endocrinol (Lausanne). 2022 Dec 15;13:992937. doi: 10.3389/fendo.2022.992937. eCollection 2022. Front Endocrinol (Lausanne). 2022. PMID: 36589841 Free PMC article. Review. - Surface cysteine to serine substitutions in IL-18 reduce aggregation and enhance activity.
Saetang J, Roongsawang N, Sangkhathat S, Voravuthikunchai SP, Sangkaew N, Prompat N, Srichana T, Tipmanee V. Saetang J, et al. PeerJ. 2022 Jul 5;10:e13626. doi: 10.7717/peerj.13626. eCollection 2022. PeerJ. 2022. PMID: 35811828 Free PMC article. - Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity.
Detry S, Andries J, Bloch Y, Gabay C, Clancy DM, Savvides SN. Detry S, et al. J Biol Chem. 2022 May;298(5):101908. doi: 10.1016/j.jbc.2022.101908. Epub 2022 Apr 6. J Biol Chem. 2022. PMID: 35398099 Free PMC article. - Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases.
Jia H, Liu J, Han B. Jia H, et al. Biomed Res Int. 2018 Apr 1;2018:3058640. doi: 10.1155/2018/3058640. eCollection 2018. Biomed Res Int. 2018. PMID: 29805973 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous