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J. Biol. Chem., Vol. 283, Issue 40, 27189-27199, October 3, 2008

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Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes^*

Alessandra Beltrami¹, Maxim Rossmann¹, Maria Teresa Fiorillo^¶, Fabiana Paladini^¶, Rosa Sorrentino^¶, Wolfram Saenger, Pravin Kumar, Andreas Ziegler², and Barbara Uchanska-Ziegler

From the Institut für Immungenetik, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Freie Universität Berlin, Thielallee 73, 14195 Berlin, Germany, the Institut für Chemie und Biochemie/Kristallographie, Freie Universität Berlin, Takustrasse 6, 14195 Berlin, Germany, and ^¶the Dipartimento di Biología Cellulare e dello Sviluppo, "Sapienza" Università di Roma, Via dei Sardi 70, 00185 Roma, Italy

Inflammatory processes are accompanied by the posttranslational modification of certain arginine residues within proteins to yield citrulline, although it is largely unknown how this modification influences antigen presentation. We employed crystallographic and functional studies to investigate whether the exchange of arginine to citrulline affects the display of a peptide by two human major histocompatibility antigen class I subtypes, HLA-B^*2705 and HLA-B^*2709. Both differ only in residue 116 within the peptide binding groove despite their differential association with ankylosing spondylitis, an inflammatory rheumatic disorder. The crystal structures described here show that a modified self-peptide, pVIPR-U5 (RRKWURWHL; U = citrulline), is presented by the two HLA-B27 molecules in distinct conformations. These binding modes differ not only drastically from each other but also from the conformations exhibited by the non-citrullinated peptide in a given subtype. The differential reactivity of HLA-B27-restricted cytotoxic T cells with modified or unmodified pVIPR supports the structural findings and shows that the presentation of citrullinated peptides has the potential to influence immune responses.

Received for publication, April 14, 2008 , and in revised form, June 19, 2008.

The atomic coordinates and structure factors (code 3B6S and 3B3I) 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 (SFB 449, B6), VolkswagenStiftung (I/79 983), Berliner Krebsgesellschaft (Ernst von Leyden fellowship to A. B.), Senate of Berlin (NaFöG fellowship to P. K.), Sonnenfeld-Stiftung, Berlin, and Fonds der Chemischen Industrie. 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-S5.

¹ Joint first authors.

² To whom correspondence should be addressed. Tel.: 49-30-8445-1817; Fax: 49-30-8445-1820; E-mail: andreas.ziegler{at}charite.de.

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