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J. Biol. Chem., Vol. 280, Issue 26, 24915-24922, July 1, 2005

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Characterization of the Interaction between Interleukin-13 and Interleukin-13 Receptors^*

Kazuhiko Arima, Kazuo Sato¶, Go Tanaka, Sachiko Kanaji, Tohru Terada||, Eijiro Honjo**, Ryota Kuroki**, Yo Matsuo¶, and Kenji Izuhara

From the Division of Medical Biochemistry, Department of Biomolecular Sciences, and the Division of Medical Research, Center for Comprehensive Community Medicine, Saga Medical School, Saga 849-8501, the Computational Proteomics Team, Protein Research Group, RIKEN Genomic Sciences Center, Yokohama 230-0045, the ^¶Graduate School of Integrated Sciences, Yokohama City University, Yokohama 230-0045, the ^||Graduate School of Agricultural and Life Sciences, Faculty of Agriculture, The University of Tokyo, Tokyo 113-8657, and the ^**Structural Biology Group, Neutron Science Research Center, Japan Atomic Energy Research Institute, Ibaraki 319-1195, Japan

Interleukin-13 (IL-13) possesses two types of receptor: the heterodimer, composed of the IL-13R1 chain (IL-13R1) and the IL-4R chain (IL-4R), transducing the IL-13 signals; and the IL-13R2 chain (IL-13R2), acting as a nonsignaling "decoy" receptor. Extracellular portions of both IL-13R1 and IL-13R2 are composed of three fibronectin type III domains, D1, D2, and D3, of which the last two comprise the cytokine receptor homology modules (CRHs), a common structure of the class I cytokine receptor superfamily. Thus far, there has been no information about the critical amino acids of the CRHs or the role of the D1 domains of IL-13R1 and IL-13R2 in binding to IL-13. In this study, we first built the homology modeling of the IL-13·hIL-13 receptor complexes and then predicted the amino acids involved in binding to IL-13. By incorporating mutations into these amino acids, we identified Tyr-207, Asp-271, Tyr-315, and Asp-318 in the CRH of human IL-13R2, and Leu-319 and Tyr-321 in the CRH of human IL-13R1, as critical residues for binding to IL-13. Tyr-315 in IL-13R2 and Leu-319 in IL-13R1 are positionally conserved hydrophobic amino acid residues. Furthermore, by using D1 domain-deleted mutants, we found that the D1 domain is needed for the expression of IL-13R2, but not IL-13R1, and that the D1 domain of IL-13R1 is important for binding to IL-13, but not to IL-4. These results provide the basis for a precise understanding of the interaction between IL-13 and its receptors.

Received for publication, March 8, 2005 , and in revised form, April 21, 2005.

^* This work was supported in part by a research grant for immunology, allergy, and organ transplant from the Ministry of Health, Welfare, and Labor of Japan, a grant-in-aid for scientific research from the Japan Society for the Promotion of Science, and a grant from Mitsubishi Pharma Research Foundation. 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.

To whom correspondence should be addressed: Division of Medical Biochemistry, Dept. of Biomolecular Sciences, Saga Medical School, Saga 849-8501, Japan. E-mail: kizuhara{at}med.saga-u.ac.jp.

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