Direct binding to integrins and loss of disulfide linkage in IL-1β are involved in the agonistic action of IL-1β

Yoko K. Takada, Jessica Yu, Masaaki Fujita, Jun Saegusa, Chun Yi Wu, Yoshikazu Takada

研究成果: 雜誌貢獻文章

2 引文 (Scopus)

摘要

There is a strong link between integrins and IL-1β, but the specifics of the role of integrins in IL-1β signaling are unclear. We describe that IL-1β specifically bound to integrins αvβ3 and α5β1. The E128K mutation in the IL1R-binding site enhanced integrin binding. We studied if direct integrin binding is involved in IL-1β signaling. We compared sequences of IL-1β and IL-1 receptor antagonist (IL1RN), which is an IL-1β homologue but has no agonistic activity. Several surface-exposed Lys residues are present in IL-1β, but not in IL1RN. A disulfide-linkage is present in IL1RN, but is not in IL-1β due to natural C117F mutation. Substitution of the Lys residues to Glu markedly reduced integrin binding of E128K IL-1β, suggesting that the Lys residues mediate integrin binding. The Lys mutations reduced, but not completely abrogated, agonistic action of IL-1β. We studied if the disulfide linkage plays a role in agonistic action of IL-1β. Re-introduction of the disulfide linkage by the F117C mutation did not affect agonistic activity of WT IL-1β, but effectively reduced the remaining agonistic activity of the Lys mutants. Also, deletion of the disulfide linkage in IL1RN by the C116F mutation did not make it agonistic. We propose that the direct binding to IL-1β to integrins is primarily important for agonistic IL-1β signaling, and that the disulfide linkage indirectly affect signaling by blocking conformational changes induced by weak integrin binding to the Lys mutants. The integrin-IL-1β interaction is a potential target for drug discovery.

原文英語
頁(從 - 到)20067-20075
頁數9
期刊Journal of Biological Chemistry
292
發行號49
DOIs
出版狀態已發佈 - 一月 1 2017

指紋

Interleukin-1
Integrins
Disulfides
Interleukin-1 Receptors
Mutation
Drug Discovery
Substitution reactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

引用此文

Direct binding to integrins and loss of disulfide linkage in IL-1β are involved in the agonistic action of IL-1β. / Takada, Yoko K.; Yu, Jessica; Fujita, Masaaki; Saegusa, Jun; Wu, Chun Yi; Takada, Yoshikazu.

於: Journal of Biological Chemistry, 卷 292, 編號 49, 01.01.2017, p. 20067-20075.

研究成果: 雜誌貢獻文章

Takada, Yoko K. ; Yu, Jessica ; Fujita, Masaaki ; Saegusa, Jun ; Wu, Chun Yi ; Takada, Yoshikazu. / Direct binding to integrins and loss of disulfide linkage in IL-1β are involved in the agonistic action of IL-1β. 於: Journal of Biological Chemistry. 2017 ; 卷 292, 編號 49. 頁 20067-20075.
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abstract = "There is a strong link between integrins and IL-1β, but the specifics of the role of integrins in IL-1β signaling are unclear. We describe that IL-1β specifically bound to integrins αvβ3 and α5β1. The E128K mutation in the IL1R-binding site enhanced integrin binding. We studied if direct integrin binding is involved in IL-1β signaling. We compared sequences of IL-1β and IL-1 receptor antagonist (IL1RN), which is an IL-1β homologue but has no agonistic activity. Several surface-exposed Lys residues are present in IL-1β, but not in IL1RN. A disulfide-linkage is present in IL1RN, but is not in IL-1β due to natural C117F mutation. Substitution of the Lys residues to Glu markedly reduced integrin binding of E128K IL-1β, suggesting that the Lys residues mediate integrin binding. The Lys mutations reduced, but not completely abrogated, agonistic action of IL-1β. We studied if the disulfide linkage plays a role in agonistic action of IL-1β. Re-introduction of the disulfide linkage by the F117C mutation did not affect agonistic activity of WT IL-1β, but effectively reduced the remaining agonistic activity of the Lys mutants. Also, deletion of the disulfide linkage in IL1RN by the C116F mutation did not make it agonistic. We propose that the direct binding to IL-1β to integrins is primarily important for agonistic IL-1β signaling, and that the disulfide linkage indirectly affect signaling by blocking conformational changes induced by weak integrin binding to the Lys mutants. The integrin-IL-1β interaction is a potential target for drug discovery.",
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AU - Yu, Jessica

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AU - Wu, Chun Yi

AU - Takada, Yoshikazu

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AB - There is a strong link between integrins and IL-1β, but the specifics of the role of integrins in IL-1β signaling are unclear. We describe that IL-1β specifically bound to integrins αvβ3 and α5β1. The E128K mutation in the IL1R-binding site enhanced integrin binding. We studied if direct integrin binding is involved in IL-1β signaling. We compared sequences of IL-1β and IL-1 receptor antagonist (IL1RN), which is an IL-1β homologue but has no agonistic activity. Several surface-exposed Lys residues are present in IL-1β, but not in IL1RN. A disulfide-linkage is present in IL1RN, but is not in IL-1β due to natural C117F mutation. Substitution of the Lys residues to Glu markedly reduced integrin binding of E128K IL-1β, suggesting that the Lys residues mediate integrin binding. The Lys mutations reduced, but not completely abrogated, agonistic action of IL-1β. We studied if the disulfide linkage plays a role in agonistic action of IL-1β. Re-introduction of the disulfide linkage by the F117C mutation did not affect agonistic activity of WT IL-1β, but effectively reduced the remaining agonistic activity of the Lys mutants. Also, deletion of the disulfide linkage in IL1RN by the C116F mutation did not make it agonistic. We propose that the direct binding to IL-1β to integrins is primarily important for agonistic IL-1β signaling, and that the disulfide linkage indirectly affect signaling by blocking conformational changes induced by weak integrin binding to the Lys mutants. The integrin-IL-1β interaction is a potential target for drug discovery.

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