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J. Biol. Chem., Vol. 280, Issue 4, 2962-2971, January 28, 2005

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Allele-dependent Similarity between Viral and Self-peptide Presentation by HLA-B27 Subtypes^*

Maria Teresa Fiorillo, Christine Rückert¶, Martin Hülsmeyer||, Rosa Sorrentino, Wolfram Saenger||**, Andreas Ziegler¶, and Barbara Uchanska-Ziegler¶

From the Dipartimento di Biologia Cellulare e dello Sviluppo, Università di Roma "La Sapienza," via dei Sardi 70, 00185 Roma, Italy, the ^¶Institut für Immungenetik, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Humboldt-Universität zu Berlin, Spandauer Damm 130, 14050 Berlin, Germany, and the ^||Institut für Chemie/Kristallographie, Freie Universität Berlin, Takustrasse 6, 14195 Berlin, Germany

Molecular mimicry is discussed as a possible mechanism that may contribute to the development of autoimmune diseases. It could also be involved in the differential association of the human major histocompatibility subtypes HLA-B^*2705 and HLA-B^*2709 with ankylosing spondylitis. These two subtypes differ only in residue 116 of the heavy chain (Asp in B^*2705 and His in B^*2709), but the reason for the differential disease association is not understood. Using x-ray crystallography, we show here that the viral peptide pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236–244) of Epstein-Barr virus) is presented by the B^*2705 and B^*2709 molecules in two drastically deviating conformations. Extensive structural similarity between pLMP2 and the self-peptide pVIPR (RRKWRRWHL, derived from vasoactive intestinal peptide type 1 receptor (residues 400–408)) is observed only when the peptides are presented by B^*2705 because of a salt bridge between Arg⁵ of both peptides and the subtype-specific heavy chain residue Asp¹¹⁶. Combined with functional studies using pLMP2/pVIPR-cross-reactive cytotoxic T cell lines and clones, together with target cells presenting these peptides or a modified peptide analogue, our results reveal that a pathogen-derived peptide can exhibit major histocompatibility complex class I subtype-dependent, drastically distinct binding modes. Furthermore, the results demonstrate that molecular mimicry between pLMP2 and pVIPR in the HLA-B27 context is an allele-dependent property.

Received for publication, September 20, 2004 , and in revised form, October 26, 2004.

The atomic coordinates and structure factors (code 1uxs and 1uxw) 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 financially supported by Deutsche Forschungsgemeinschaft Grant SFB 449, TP B5,B6; Sonnenfeld-Stiftung; COFIN 2001; and Istituto Pasteur Fondazione Cenci-Bolognetti. 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 may be addressed. Tel.: 49-30-8385-3412; Fax: 49-30-8385-6702; E-mail: saenger{at}chemie.fu-berlin.de. To whom correspondence may be addressed. Tel.: 49-30-4505-53517; Fax: 49-30-4505-53953; E-mail: barbara.uchanska-ziegler{at}charite.de.

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