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The Exon-3-Encoded Domain of IL-15Rα Contributes to IL-15 High-Affinity Binding and Is Crucial for the IL-15 Antagonistic Effect of Soluble IL-15Rα

Abstract : We previously showed that a natural soluble form of interleukin-15 (IL-15) Rα corresponding to the full-length ectodomain of IL-15Rα behaved as a potent antagonist of IL-15 action through IL-15Rα/β/γ, whereas a re-combinant soluble IL-15Rα sushi domain did not, but instead acted as an agonist of IL-15 action through IL-15Rβ/γ. In order to determine precisely the molecular basis governing these antagonistic versus agonistic actions, we compared the binding properties and biological effects of recombinant soluble IL-15Rα (sIL-15Rα) species containing the sushi domain and different remaining parts of the ectodomain. We first demonstrate that the exon-3-encoded domain and, more particularly, its N-terminal 13-amino-acid (aa) peptide are important, in addition to the adjacent exon-2-encoded sushi domain, for the stabilization of the high-affinity IL-15·IL-15Rα complex by slowing down its dissociation rate and by contributing to about 10-20% of the free energy of interaction. We next show that all sushi-containing sIL-15Rα are agonists on IL-15Rβ/γ, coordinately increasing IL-15 binding and IL-15-induced proliferation. Their agonistic potencies are proportional to their respective affinities for IL-15. We then show that the antagonistic effect of sIL-15Rα in the context of IL-15Rα/β/γ is due to the 13-aa peptide that creates a sterical constraint impeding the binding of the sIL-15Rα·IL-15 complex to the membrane-anchored IL-15Rα/β/γ. In the frame of the soluble IL-15Rα sushi domain-IL-15 fusion protein that contains the 13-aa peptide, this constraint is alleviated as a result of a conformational effect due to the covalent linking of the 13-aa peptide to the N-terminus of IL-15. The soluble IL-15Rα sushi domain-IL-15 fusion protein is therefore able to bind and activate both the IL-15Rβ/γ and the IL-15Rα/β/γ receptors.
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https://www.hal.inserm.fr/inserm-02533457
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Submitted on : Monday, April 6, 2020 - 2:28:31 PM
Last modification on : Tuesday, April 7, 2020 - 2:07:03 AM

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Grégory Bouchaud, Laure Garrigue-Antar, Véronique Solé, Agnès Quéméner, Yvan Boublik, et al.. The Exon-3-Encoded Domain of IL-15Rα Contributes to IL-15 High-Affinity Binding and Is Crucial for the IL-15 Antagonistic Effect of Soluble IL-15Rα. Journal of Molecular Biology, Elsevier, 2008, ⟨10.1016/j.jmb.2008.07.019⟩. ⟨inserm-02533457⟩

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