title: pH stability of HLA-DR4 complexes with antigenic peptides.
abstract: Complexes between antigenic peptides and class II proteins of the major histocompatibility complex (MHC) trigger cellular immune responses. These complexes usually dissociate more rapidly at mildly acidic pH, where they are formed intracellularly, as compared to neutral pH, where they function at the cell surface. This paper describes the pH dependence of the dissociation kinetics of complexes between MHC proteins and antigenic peptides containing aspartic and glutamic acid residues. Some of these complexes show an unusual pH dependence, dissociating much more rapidly at pH 7 than at pH 5.3. This occurs when the carboxylate group of the aspartic or glutamic acid residue is located in a neutral pocket of the protein. In contrast, solvent-exposed carboxylate groups or carboxylate groups buried in pockets where they form salt bridges with the protein do not show this unusual pH dependence. The kinetic data having the unusual pH dependence conform closely to a model in which there is a rapid reversible equilibration between a less stable deprotonated complex and a more stable protonated complex. In this model, the pK(a) of the protonation reaction for the partially buried peptide carboxylate group ranges from 7.7 to 8.3, reflecting the strongly basic conditions required for deprotonation. One of the few peptide/MHC complexes demonstrated to play a role in autoimmunity in humans contains a buried peptide carboxylate and shows this unusual pH dependence. The relevance of this finding to understanding the chemical basis of autoimmunity is briefly discussed.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Belmares
authors.forename: J D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: E D
authors.initials: ED
authors.lastname: Mellins
authors.forename: H M
authors.initials: HM
authors.lastname: McConnell
mesh_terms: D054392:Adipokines; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1; D051184:Desmoglein 3; D018698:Glutamic Acid / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D037102:Lectins; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010392:Pemphigus / Q000276:immunology; D010455:Peptides / Q000276:immunology* / Q000378:metabolism*; D011522:Protons; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility
chemical_list: D054392:Adipokines; D001324:Autoantigens; C084533:CHI3L1 protein, human; D015820:Cadherins; D000071451:Chitinase-3-Like Protein 1; C071894:DSG3 protein, human; D051184:Desmoglein 3; D006023:Glycoproteins; D015804:HLA-DR4 Antigen; D037102:Lectins; D010455:Peptides; D011522:Protons; D011994:Recombinant Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid