title: Enhanced catalytic action of HLA-DM on the exchange of peptides lacking backbone hydrogen bonds between their N-terminal region and the MHC class II alpha-chain.
abstract: The class II MHC homolog HLA-DM catalyzes exchange of peptides bound to class II MHC proteins, and is an important component of the Ag presentation machinery. The mechanism of HLA-DM-mediated catalysis is largely obscure. HLA-DM catalyzes exchange of peptides of varying sequence, suggesting that a peptide sequence-independent component of the MHC-peptide interaction could be involved in the catalytic process. Twelve conserved hydrogen bonds between the peptide backbone and the MHC are a prominent sequence-independent feature of the MHC-peptide interaction. To evaluate the relative importance of these hydrogen bonds toward HLA-DM action, we prepared peptide variants that lacked the ability to form one or more of the hydrogen bonds as a result of backbone amide N-methylation or truncation, and tested their ability to be exchanged by HLA-DM. We found that disruption of hydrogen bonds involving HLA-DR1 residues alpha51-53, a short extended segment at the N terminus of the alpha subunit helical region, led to heightened HLA-DM catalytic efficacy. We propose that those bonds are disrupted in the MHC conformation recognized by HLA-DM to allow structural transitions in that area during DM-assisted peptide release. These results suggest that peptides or compounds that bind MHC but cannot form these interactions would be preferentially edited out by HLA-DM.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Stratikos@crystal.harvard.edu
authors.forename: Efstratios
authors.initials: E
authors.lastname: Stratikos
authors.forename: Don C
authors.initials: DC
authors.lastname: Wiley
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis; D017124:Conserved Sequence; D006681:HLA-D Antigens / Q000378:metabolism* / Q000502:physiology; D015798:HLA-DR1 Antigen / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D011487:Protein Conformation; D017393:RNA Editing / Q000276:immunology
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015798:HLA-DR1 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments