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J. Biol. Chem., Vol. 278, Issue 39, 37730-37735, September 26, 2003

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The Crystal Structure of the Major Cat Allergen Fel d 1, a Member of the Secretoglobin Family^*

Liselotte Kaiser  , Hans Grönlund  , Tatyana Sandalova  ¶, Hans-Gustaf Ljunggren ||, Marianne van Hage-Hamsten , Adnane Achour || ** and Gunter Schneider ¶

From the Department of Medicine, Unit of Clinical Immunology and Allergy, Karolinska Institutet and Hospital L2:04, S-171 76 Stockholm, Sweden, ^¶Department of Medical Biochemistry and Biophysics, Scheelev 2, S-171 77 Stockholm, Sweden, and ^||Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Huddinge University Hospital, S-141 86 Stockholm, Sweden

The domestic cat (Felis domesticus) is one of the most important causes of allergic asthma worldwide. The dominating cat allergen, Fel d 1, is composed of two heterodimers. Recently, it has been shown that recombinant Fel d 1, consisting of chain 2 and chain 1 fused together without additional linker, has immunological properties indistinguishable from the natural heterodimeric protein. Herein, we report the crystal structure of recombinant monomeric Fel d 1 at 1.85-Å resolution, determined by multi-wavelength anomalous diffraction using selenomethionine substituted protein. Fel d 1 is an all-helical protein and consists of eight helices. The two halves of the recombinant Fel d 1 molecule, corresponding to the wild-type Fel d 1 chains, are very similar in three-dimensional structure, despite the lack of significant sequence identity. The structure of the Fel d 1 presents a striking similarity to that of uteroglobin, a steroid-inducible cytokine-like molecule with anti-inflammatory and immunomodulatory properties. An internal, asymmetric cavity is formed in the Fel d 1 that could bind an endogenous ligand. The distribution of residues lining this cavity suggests that such a ligand must be amphipathic. The structure of Fel d 1 displays the localization of three previously defined Fel d 1 IgE epitopes on the surface of the protein. The three-dimensional structure provides a framework for rational design of hypoallergenic mutants aimed for treatment of cat allergy.

Received for publication, May 7, 2003 , and in revised form, July 3, 2003.

The atomic coordinates and structure factors (code 1PUO) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* Financial support for this study was received from the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Foundation for Health Care Sciences and Allergy Research, the Åke Wibergs Foundation, the Magnus Bergwalls Foundation, the Swedish Asthma and Allergy Association, the Hesselman Foundation, the Swedish-Heart Lung Foundation, and the King Gustaf V 80th Birthday 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 46-8-58589635; Fax: 46-8-7467637; E-mail: adnane.achour{at}mtc.ki.se.

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