Molecular determinants of major histocompatibility complex class I complex stability: shaping antigenic features through short and long range electrostatic interactions.

Abstract

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 pOmega, as found in gag (KRWIILGLNK; viral), additionally stabilizes the B(*)2705 complexes by approximately 5 and approximately 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 approximately 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.

• Authors: Daniele Narzi, Kathrin Winkler, Jürgen Saidowsky, Rolf Misselwitz, Andreas Ziegler, Rainer A Böckmann, Ulrike Alexiev
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 34 Pg. 23093-103 (Aug 22 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18505734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-B27 Antigen
• Ligands
• Peptides
• Aspartic Acid
• Arginine
• Lysine

Topics

• Allosteric Site
• Amino Acid Sequence
• Arginine (chemistry)
• Aspartic Acid (chemistry)
• Genes, MHC Class I
• HLA-B27 Antigen (genetics)
• Humans
• Hydrogen-Ion Concentration
• Ligands
• Lysine (chemistry)
• Models, Biological
• Molecular Sequence Data
• Peptides (chemistry)
• Spectrometry, Fluorescence (methods)
• Static Electricity