Cutting edge: HLA-DM-mediated peptide exchange functions normally on MHC class II-peptide complexes that have been weakened by elimination of a conserved hydrogen bond.
The mechanism by which HLA-DM (DM) promotes exchange of peptides bound to HLA-DR (DR) is still unclear. We have shown that peptide interaction with DR1 can be considered a folding process as evidenced by cooperativity. However, in DM-mediated ligand exchange, prebound peptide release is noncooperative, which could be a function of the breaking of a critical interaction. The hydrogen bond (H-bond) between beta-chain His(81) and the peptide backbone at the -1 position is a candidate for such a target. In this study, we analyze the exchange of peptides bound to a DR1 mutant in which formation of this H-bond is impaired. We observe that DM still functions normally. However, as expected of a cooperative model, this H-bond contributes to the overall energetics of the complex and its disruption impacts the ability of the exchange ligand to fold with the binding groove into a stable complex.
Ferrante
Andrea
A
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA. andrea.ferrante@bcw.edu
Gorski
Jack
J
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D006681:HLA-D Antigens / Q000378:metabolism / Q000502:physiology*; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D009980:Influenza A virus / Q000276:immunology; D008024:Ligands; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008024:Ligands; D046912:Multiprotein Complexes; D010446:Peptide Fragments