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J. Biol. Chem., Vol. 281, Issue 4, 2306-2316, January 27, 2006

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Conformational Dimorphism of Self-peptides and Molecular Mimicry in a Disease-associated HLA-B27 Subtype^*

Christine Rückert12, Maria Teresa Fiorillo1, Bernhard Loll¶13, Roberto Moretti, Jacek Biesiadka¶, Wolfram Saenger¶, Andreas Ziegler, Rosa Sorrentino4, and Barbara Uchanska-Ziegler5

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

An interesting property of certain peptides presented by major histocompatibility complex (MHC) molecules is their acquisition of a dual binding mode within the peptide binding groove. Using x-ray crystallography at 1.4 Å resolution, we show here that the glucagon receptor-derived self-peptide pGR (⁴¹²RRRWHRWRL⁴²⁰) is presented by the disease-associated human MHC class I subtype HLA-B^*2705 in a dual conformation as well, with the middle of the peptide bent toward the floor of the peptide binding groove of the molecule in both binding modes. The conformations of pGR are compared here with those of another self-peptide (pVIPR, RRKWRRWHL) that is also displayed in two binding modes by HLA-B^*2705 antigens and with that of the viral peptide pLMP2 (RRRWRRLTV). Conserved structural features suggest that the N-terminal halves of the peptides are crucial in allowing cytotoxic T lymphocyte (CTL) cross-reactivity. In addition, an analysis of T cell receptors (TCRs) from pGR- or pVIPR-directed, HLA-B27-restricted CTL clones demonstrates that TCR from distinct clones but with comparable reactivity may share CDR3 but not CDR3 regions. Therefore, the cross-reactivity of these CTLs depends on TCR-CDR3, is modulated by TCR-CDR3 sequences, and is ultimately a consequence of the conformational dimorphism that characterizes binding of the self-peptides to HLA-B^*2705. These results lend support to the concept that conformational dimorphisms of MHC class I-bound peptides might be connected with the occurrence of self-reactive CTL.

Received for publication, August 3, 2005 , and in revised form, September 26, 2005.

The atomic coordinates and structure factors (code 2A83) 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 the Deutsche Forschungsgemeinschaft (Grant SFB449/B6,Z3 to W. S., A. Z., and B. U.-Z.), Volkswagen-Stiftung (Grant I/79 989 to A. Z. and R. S.), 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.

¹ These authors contributed equally to this work.

² Present address: Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.

³ Present address: Max-Planck-Institut für Medizinische Forschung, Abteilung für Biomolekulare Mechanismen, 69126 Heidelberg, Germany.

⁴ To whom correspondence may be addressed. Tel.: 39-06-4991-7706; Fax: 39-06-4991-7594; E-mail: rosa.sorrentino{at}uniroma1.it. ⁵ 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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