Crystal structure of the interleukin-15·interleukin-15 receptor α complex: Insights into trans and cis presentation

Shaun K. Olsen, Naruhisa Ota, Seiichiro Kishishita, Mutsuko Kukimoto-Niino, Kazutaka Murayama, Hidemi Uchiyama, Mitsutoshi Toyama, Takaho Terada, Mikako Shirouzu, Osami Kanagawa, Shigeyuki Yokoyama

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65 Citations (Scopus)

Abstract

Interleukin (IL)-15 is a pleiotropic cytokine that plays a pivotal role in both innate and adaptive immunity. IL-15 is unique among cytokines due to its participation in a trans signaling mechanism in which IL-15 receptor α (IL-15Rα) from one subset of cells presents IL-15 to neighboring IL-2Rβ/γc-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15Rα. The structure reveals that the α receptor-binding epitope of IL-15 adopts a unique conformation, which, together with amino acid substitutions, permits specific interactions with IL-15Rα that account for the exceptionally high affinity of the IL-15·IL-15Rα complex. Interestingly, analysis of the topology of IL-15 and IL-15Rα at the IL-15·IL-15Rα interface suggests that IL-15 should be capable of participating in a cis signaling mechanism similar to that of the related cytokine IL-2. Indeed, we present biochemical data demonstrating that IL-15 is capable of efficiently signaling in cis through IL-15Rα and IL-2Rβ/γc expressed on the surface of a single cell. Based on our data we propose that cis presentation of IL-15 may be important in certain biological contexts and that flexibility of IL-15Rα permits IL-15 and its three receptor components to be assembled identically at the ligand-receptor interface whether IL-15 is presented in cis or trans. Finally, we have gained insights into IL-15·IL-15Rα·IL-2Rβ·γc quaternary complex assembly through the use of molecular modeling.

Original languageEnglish
Pages (from-to)37191-37204
Number of pages14
JournalJournal of Biological Chemistry
Volume282
Issue number51
DOIs
Publication statusPublished - 2007 Dec 21

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Olsen, S. K., Ota, N., Kishishita, S., Kukimoto-Niino, M., Murayama, K., Uchiyama, H., Toyama, M., Terada, T., Shirouzu, M., Kanagawa, O., & Yokoyama, S. (2007). Crystal structure of the interleukin-15·interleukin-15 receptor α complex: Insights into trans and cis presentation. Journal of Biological Chemistry, 282(51), 37191-37204. https://doi.org/10.1074/jbc.M706150200