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Mol Immunol. 2012 Feb;50(1-2):26-34. doi: 10.1016/j.molimm.2011.11.014. Epub 2011 Dec 23.

DRB1*12:01 presents a unique subset of epitopes by preferring aromatics in pocket 9.

Author information

1
Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101, USA. ichow@benaroyaresearch.org

Abstract

This study characterized the unique peptide-binding characteristics of HLA-DRB1*12:01 (DR1201), an allele studied in the context of various autoimmune diseases, using a peptide competition assay and structural modeling. After defining Influenza A/Puerto Rico/8/34 Matrix Protein M1 (H1MP) 40-54 as a DR1201 restricted epitope, the critical anchor residues within this sequence were confirmed by measuring the relative binding of peptides with non-conservative substitutions in competition with biotin labeled H1MP(40-54) peptide. Based on this information, a set of peptides was designed with single amino acid substitutions at these anchor positions. The overall peptide binding preferences for the DR1201 allele were deduced by incubating these peptides in competition with the reference H1MP(40-54) to determine the relative binding affinities of each to recombinant DR1201 protein. As expected, pocket 1 preferred methionine and aliphatic residues, and tolerated phenylalanine. Pocket 4 was mostly composed of hydrophobic residues, thereby preferentially accommodating aliphatic residues, but could also weakly accommodate lysine due to its slightly acidic environment. Pocket 6 accepted a wide range of amino acids because of the diverse residues that comprise this pocket. Pocket 9 accepted aliphatic and negatively charged amino acids, but showed a remarkable preference for aromatic residues due to the conformation of the pocket, which lacks the typical salt bridge between β57Asp and α76Arg. These binding characteristics contrast with the closely related DR1104 allele, distinguishing DR1201 among the alleles of the HLA-DR5 group. These empirical results were used to develop an algorithm to predict peptide binding to DR1201. This algorithm was used to verify T cell epitopes within novel antigenic peptides identified by tetramer staining and within peptides from published reports that contain putative DR1201 epitopes.

PMID:
22196942
PMCID:
PMC3433834
DOI:
10.1016/j.molimm.2011.11.014
[Indexed for MEDLINE]
Free PMC Article

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