Functional Relevance of Interleukin-1 Receptor Inter-domain Flexibility for Cytokine Binding and Signaling
Copyright © 2019 Elsevier Ltd. All rights reserved..
The interleukin 1 (IL-1) receptor family, whose members contain three immunoglobulin-like domains (D1-D3) in the extracellular region, is responsible for transmitting pleiotropic signals of IL-1 cytokines. The inter-domain flexibility of IL-1 receptors and its functional roles have not been fully elucidated. In this study, we used small-angle X-ray scattering to show that ligand-binding primary receptors and co-receptors in the family all have inherent inter-domain flexibility due to the D2/D3 linker. Variants of the IL-1RAcP and IL-18Rβ co-receptors with mutated D2/D3 linkers cannot form a cytokine-receptor complex and mediate signaling. Our analysis further revealed that these mutated co-receptors exhibited a changed conformational ensemble, suggesting that loss of function is due to the alteration of receptor dynamics. Taken together, our results demonstrate that the D2/D3 linker is a critical functional determinant of IL-1 receptor and underscore the important roles of the inter-domain flexibility in cytokine/receptor binding and signaling.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Structure (London, England : 1993) - 27(2019), 8 vom: 06. Aug., Seite 1296-1307.e5 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ge, Jiwan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.05.2020 Date Revised 06.08.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.str.2019.05.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 245 | 1 | 0 | |a Functional Relevance of Interleukin-1 Receptor Inter-domain Flexibility for Cytokine Binding and Signaling |
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| 500 | |a Date Revised 06.08.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Ltd. All rights reserved. | ||
| 520 | |a The interleukin 1 (IL-1) receptor family, whose members contain three immunoglobulin-like domains (D1-D3) in the extracellular region, is responsible for transmitting pleiotropic signals of IL-1 cytokines. The inter-domain flexibility of IL-1 receptors and its functional roles have not been fully elucidated. In this study, we used small-angle X-ray scattering to show that ligand-binding primary receptors and co-receptors in the family all have inherent inter-domain flexibility due to the D2/D3 linker. Variants of the IL-1RAcP and IL-18Rβ co-receptors with mutated D2/D3 linkers cannot form a cytokine-receptor complex and mediate signaling. Our analysis further revealed that these mutated co-receptors exhibited a changed conformational ensemble, suggesting that loss of function is due to the alteration of receptor dynamics. Taken together, our results demonstrate that the D2/D3 linker is a critical functional determinant of IL-1 receptor and underscore the important roles of the inter-domain flexibility in cytokine/receptor binding and signaling | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a IL-1 receptor family | |
| 650 | 4 | |a dual-luciferase reporter assay | |
| 650 | 4 | |a inter-domain flexibility | |
| 650 | 4 | |a minimal ensemble search | |
| 650 | 4 | |a signal transduction | |
| 650 | 4 | |a small-angle X-ray scattering (SAXS) | |
| 650 | 7 | |a Receptors, Interleukin-1 |2 NLM | |
| 700 | 1 | |a Remesh, Soumya G |e verfasserin |4 aut | |
| 700 | 1 | |a Hammel, Michal |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Si |e verfasserin |4 aut | |
| 700 | 1 | |a Mahan, Andrew D |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuying |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xinquan |e verfasserin |4 aut | |
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