Cutting edge: a single, essential hydrogen bond controls the stability of peptide-MHC class II complexes.
The binding of peptides to MHC class II molecules is mediated in part by a conserved array of intermolecular hydrogen bonds. We have evaluated the consequences of disrupting the hydrogen bond between beta-His-81 of the class II molecule and bound peptide. These studies revealed that peptide dissociation rates were accelerated by factors ranging to 200-fold. The sensitivity of a peptide to loss of the hydrogen bond is inversely correlated with the inherent kinetic stability of the peptide-MHC complex. The same relationship has been observed between inherent kinetic stability and the susceptibility to DM. Given that the rate enhancement observed for MHC class II I-Ad protein mutated at position 81 in the beta-chain is comparable with DM-catalyzed rates for other class II molecules, we suggest that DM could function by stabilizing a peptide-MHC intermediate in which one or more hydrogen bonds between the peptide and MHC, such as that contributed by the beta-His-81 hydrogen bond, are disrupted.
McFarland
B J
BJ
Department of Chemistry, University of Washington, Seattle 98195, USA.
Beeson
C
C
Sant
A J
AJ
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D046911:Macromolecular Substances; D010446:Peptide Fragments; C045084:invariant chain