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A pH-sensitive histidine residue as control element for ligand release from HLA-DR molecules

Item Type:Article
Title:A pH-sensitive histidine residue as control element for ligand release from HLA-DR molecules
Creators Name:Roetzschke, O. and Lau, J.M. and Hofstätter, M. and Falk, K. and Strominger, J.L.
Abstract:Class II MHC molecules undergo conformational changes on shifts of the pH. As a consequence, low-affinity peptides tightly bound at pH 7.0 can be released at pH 5.0. The imidazole group of histidine is the only amino acid side chain affected within this range. At pH 5.0 the group is positively charged, polar, and hydrophilic, whereas at pH 7.4 it is neutral, apolar, and hydrophobic. In this study, we used soluble forms of HLA-DR and substituted conserved histidine residues with tyrosine, an isosteric analogue to the uncharged form of histidine. The goal of this substitution was to identify crucial His residues by an increase in pH stability of the ligand complex. HLA-DM-mediated release experiments revealed that substitution of His-33 in the {alpha}1 domain of the HLA-DR molecule almost doubled the half-life of HLA-DR1/class II-associated invariant-chain peptide complexes. The divergence in the off-rate of WT and H33Y mutated complex was strictly pH-dependent and correlated with the theoretical titration curve of the imidazole group. For both HLA-DR1 and HLA-DR4 molecules the mutation resulted in a shift of class II-associated invariant-chain peptide release curves by up to 0.5 pH units. His-33{alpha}1 is present in all HLA-DR and H-2E molecules. It connects the {alpha}1 and {alpha}2 domains in its noncharged form by hydrophobic interactions with residue Val-136{alpha}2. It is located in close proximity to the putative interface with HLA-DM and may function as a pH-sensitive "button," which is closed at pH 7.0 but opens below pH 6.0 to allow conformational transitions necessary for ligand exchange.
Keywords:Amino Acid Sequence, B-Lymphocyte Differentiation Antigens, Histidine, Histocompatibility Antigens Class II, HLA-D Antigens, HLA-DP Antigens, HLA-DQ Antigens, HLA-DR Antigens, Hydrogen-Ion Concentration, Ligands, Molecular Sequence Data, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:16946-16950
Date:24 December 2002
Official Publication:https://doi.org/10.1073/pnas.212643999
PubMed:View item in PubMed

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