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J. Biol. Chem., Vol. 280, Issue 29, 27069-27075, July 22, 2005

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A Structural Basis for CD8⁺ T Cell-dependent Recognition of Non-homologous Peptide Ligands

IMPLICATIONS FOR MOLECULAR MIMICRY IN AUTOREACTIVITY^*

Tatyana Sandalova, Jakob Michaëlsson¶, Robert A. Harris||, Jacob Odeberg**, Gunter Schneider, Klas Kärre¶, and Adnane Achour

From the Department of Medical Biochemistry and Biophysics, ^¶Microbiology and Tumor Biology Center, and Strategic Research Center IRIS for Studies of Integrated Recognition in the Immune System, Karolinska Institutet, SE-171 77 Stockholm, Sweden, ^||Center for Molecular Medicine, Karolinska University Hospital Solna, SE-171 77 Stockholm, Sweden, ^**Department of Biochemistry, Royal School of Technology, SE-100 44 Stockholm, Sweden, and Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden

Molecular mimicry of self-epitopes by viral antigens is one possible pathogenic mechanism underlying induction of autoimmunity. A self-epitope, mDBM, derived from mouse dopamine -mono-oxygenase (KALYDYAPI) sharing 44% sequence identity with the lymphocytic choriomeningitis virus-derived immunodominant epitope gp33 (KAVYNFATC/M), has previously been identified as a cross-reactive self-ligand, presentation of which results in autoimmunity. A rat peptide homologue, rDBM (KALYNYAPI, 56% identity to gp33), which displayed similar properties to mDBM, has also been identified. We herein report the crystal structure of H-2D^b·rDBM and a comparison with the crystal structures of the cross-reactive H-2D^b·gp33 and non-cross-reactive H-2D^b·gp33 (V3L) escape variant (KALYNFATM, 88% identity to gp33). Despite the large sequence disparity, rDBM and gp33 peptides are presented in nearly identical manners by H-2D^b, with a striking juxtaposition of the central sections of both peptides from residues p3 to p7. The structural similarity provides H-2D^b in complex with either a virus-derived or a dopamine -mono-oxygenase-derived peptide with a shared antigenic identity that conserves the positioning of the heavy chain and peptide residues that interact with the T cell receptor (TCR). This stands in contrast to the structure of H-2D^b·gp33 (V3L), in which a single conserved mutation, also present in rDBM, induces large movements of both the peptide backbone and the side chains that interact with the TCR. The TCR-interacting surfaces of the H-2D^b·rDBM and H-2D^b·gp33 major histocompatibility complexes are very similar with regard to shape, topology, and charge distribution, providing a structural basis for CD8 T cell activation by molecular mimicry and potential subsequent development of autoreactivity.

Received for publication, January 25, 2005

The atomic coordinates and structure factors (code 1ZHB) 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 grants from the Swedish Research Council, the Swedish Cancer Society, the Åke Wiberg, the Magnus Bergwall, the Alex and Ewa Wallström Foundations, and the Swedish Foundation for Strategic Research. 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: Center for Infectious Medicine, Dept. of Medicine F59, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. Tel.: 46-8-5858-9443; Fax: 46-8-746-7637; E-mail: adnane.achour{at}medhs.ki.se.

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