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
Department of Pathology
Amino Acid Sequence; Catalysis; Conserved Sequence; HLA-D Antigens; HLA-DR1 Antigen; Hemagglutinin Glycoproteins, Influenza Virus; Histocompatibility Antigens Class II; Humans; Hydrogen Bonding; Intracellular Fluid; Kinetics; Molecular Sequence Data; Peptide Fragments; Protein Conformation; RNA Editing
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Immunol. 2004 Jan 15;172(2):1109-17.
Journal of immunology (Baltimore, Md. : 1950)
Stratikos, Efstratios; Wiley, Don C.; and Stern, Lawrence J., "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" (2004). Open Access Articles. 1108.