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J. Biol. Chem., Vol. 282, Issue 51, 37191-37204, December 21, 2007

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Crystal Structure of the Interleukin-15·Interleukin-15 Receptor 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, and Shigeyuki Yokoyama^||1

From the RIKEN Genomic Sciences Center and the RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, the ^¶Tohoku University Biomedical Engineering Research Organization, Sendai 980-8575, and the ^||Department of Biophysics and Biochemistry, University of Tokyo, Tokyo 113-0033, Japan

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 (IL-15R) from one subset of cells presents IL-15 to neighboring IL-2Rβ/_c-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15R. The structure reveals that the receptor-binding epitope of IL-15 adopts a unique conformation, which, together with amino acid substitutions, permits specific interactions with IL-15R that account for the exceptionally high affinity of the IL-15·IL-15R complex. Interestingly, analysis of the topology of IL-15 and IL-15R at the IL-15·IL-15R 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-15R and IL-2Rβ/_c 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-15R 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-15R·IL-2Rβ·_c quaternary complex assembly through the use of molecular modeling.

Received for publication, July 26, 2007 , and in revised form, September 28, 2007.

The atomic coordinates and structure factors (code 2PSM) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the RIKEN Structural Genomics/Proteomics Initiative, the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and an additional reference.

¹ To whom correspondence should be addressed. Tel.: 81-45-503-9196; Fax: 81-45-503-9195; E-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp.

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