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J. Biol. Chem., Vol. 283, Issue 34, 23093-23103, August 22, 2008

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Molecular Determinants of Major Histocompatibility Complex Class I Complex Stability

SHAPING ANTIGENIC FEATURES THROUGH SHORT AND LONG RANGE ELECTROSTATIC INTERACTIONS^*

Daniele Narzi¹, Kathrin Winkler¹, Jürgen Saidowsky, Rolf Misselwitz^¶, Andreas Ziegler^¶, Rainer A. Böckmann², and Ulrike Alexiev³

From the Theoretical and Computational Membrane Biology, Center for Bioinformatics, Universität des Saarlandes, P. O. Box 15 11 50, D-66041 Saarbrücken, the Physics Department, Freie Universität Berlin, Arnimallee 14, D-14195 Berlin, and the ^¶Institut für Immungenetik, Charité Universitätsmedizin Berlin, Freie Universität zu Berlin, Thielallee 73, D-14195 Berlin, Germany

A single amino acid exchange between the major histocompatibility complex molecules HLA-B^*2705 and HLA-B^*2709 (Asp-116/His) is responsible for the emergence of distinct HLA-B27-restricted T cell repertoires in individuals harboring either of these two subtypes and could correlate with their differential association with the autoimmune disease ankylosing spondylitis. By using fluorescence depolarization and pK_a calculations, we investigated to what extent electrostatic interactions contribute to shape antigenic differences between these HLA molecules complexed with viral, self, and non-natural peptide ligands. In addition to the established main anchor of peptides binding to HLA-B27, arginine at position 2 (pArg-2), and the secondary anchors at the peptide termini, at least two further determinants contribute to stable peptide accommodation. 1) The interaction of Asp-116 with arginine at peptide position 5, as found in pLMP2 (RRRWRRLTV; viral) and pVIPR (RRKWRRWHL; self), and with lysine in p, as found in gag (KRWIILGLNK; viral), additionally stabilizes the B^*2705 complexes by 5 and 27 kJ/mol, respectively, in comparison with B^*2709. 2) The protonation state of the key residues Glu-45 and Glu-63 in the B-pocket, which accommodates pArg-2, affects peptide binding strength in a peptide- and subtype-dependent manner. In B^*2705/pLMP2, protonation of Glu-45/Glu-63 reduces the interaction energy of pArg-2 by 24 kJ/mol as compared with B^*2705/pVIPR. B^*2705/pVIPR is stabilized by a deprotonated Glu-45/Glu-63 pair, evoked by allosteric interactions with pHis-8. The mutual electrostatic interactions of peptide and HLA molecule, including peptide- and subtype-dependent protonation of key residues, modulate complex stability and antigenic features of the respective HLA-B27 subtype.

Received for publication, December 17, 2007 , and in revised form, April 18, 2008.

^* This work was supported by VolkswagenStiftung Grant I/79 983 (to U. A., R. B., and A. Z.) and in part by Deutsche Forschungsgemeinschaft Grant Sfb 449 TPA5 (to U. A.), Deutsche Forschungsgemeinschaft Grant BIZ 4/1 (to R. A. B.), and European Union Grant EFRE 2000-2006 2ü/2 (to A. Z.). 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 Tables S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 49-681-302-64169; Fax: 49-681-302-64180; E-mail: rainer{at}bioinformatik.uni-saarland.de. ³ To whom correspondence should be addressed. Tel.: 49-30-838-55157; Fax: 49-30-83856299; E-mail: alexiev{at}physik.fu-berlin.de.

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