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Originally published In Press as doi:10.1074/jbc.M513118200 on January 5, 2006 Originally published In Press as doi:10.1074/jbc.M513118200 on December 23, 2005

J. Biol. Chem., Vol. 281, Issue 10, 6642-6647, March 10, 2006
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The Structure of the Interleukin-15{alpha} Receptor and Its Implications for Ligand Binding*

Inken Lorenzen{ddagger}, Andrew J. Dingley§, Yannick Jacques, and Joachim Grötzinger{ddagger}1

From the {ddagger}Biochemisches Institut der Christian-Albrechts-Universität Kiel, Olshausenstrasse 40, 24118 Kiel, Germany, §Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom, and INSERM, UMR 601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes F-44093, France

Interleukin (IL)-15 is a member of the small four {alpha}-helix bundle family of cytokines. IL-15 was discovered by its ability to mimic IL-2-mediated T-cell proliferation. Both cytokines share the beta and {gamma} receptor chains of the IL-2 receptor for signal transduction. However, in addition, they target specific {alpha} chain receptors IL-15R{alpha} and IL-2R{alpha}, respectively. The exceptionally high affinity binding of IL-15 to IL-15R{alpha} is mediated by its sushi domain. Here we present the solution structure of the IL-15R{alpha} sushi domain solved by NMR spectroscopy and a model of its complex with IL-15. The model shows that, rather than the familiar hydrophobic forces dominating the interaction interface between cytokines and their cognate receptors, the interaction between the IL-15 and IL-15R{alpha} complex involves a large network of ionic interactions. This type of interaction explains the exceptionally high affinity of the IL-15·IL-15R{alpha} complex, which is essential for the biological effects of this important cytokine and which is not observed in other cytokine/cytokine receptor complexes.

Received for publication, December 8, 2005

The atomic coordinates and structure factors (code 2ERS) 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 a grant of the Deutsche Forschungsgemeinschaft (SFB 415). 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.

1 To whom correspondence should be addressed: Biochemisches Institut, Christian-Albrechts-Universität Kiel, Olshausenstr. 40, D-24118 Kiel, Germany. Tel.: 49-431-8801686; Fax: 49-431-8805007; E-mail: jgroetzinger{at}biochem.uni-kiel.de.


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