Residue 81 confers a restricted C-terminal peptide binding motif in HLA-B*44:09.
Knowledge about the magnitude of individual polymorphism is a critical part in understanding the complexity of comprehensive mismatching. HLA-B*44:09 differs from the highly frequent HLA-B*44:02 allele by amino acid exchanges at residues 77, 80, 81, 82 and 83. We aimed to identify the magnitude of these mismatches on the features of HLA-B*44:09 bound peptides since residues 77, 80 and 81 comprise part of the F pocket which determines sequence specificity at the pΩ position of the peptide. Using soluble HLA technology we determined >200 individual (nonduplicate) self-peptides from HLA-B*44:09 and compared their features with that of the published peptide features of HLA-B*44:02. Both alleles illustrate an anchor motif of E at p2. In contrast to the C-terminal peptide binding motif of B*44:02 (W, F, Y or L), B*44:09-derived peptides are restricted predominantly to L or F. The source of peptides for both alleles is identical (LCL 721.221 cells) allowing us to identify 23 shared peptides. The majority of these peptides however contained the restricted B*44:09 anchor motif of F or L at the pΩ position. Molecular modelling based on the B*44:02 structure highlights that the differences of the C-terminal peptide anchor between both alleles can be explained primarily by the B*44:02(81Ala) > B*44:09(81Leu) polymorphism which restricts the size of the amino acid that can be accommodated in the F pocket of B*44:09. These results highlight that every amino acid substitution has an impact of certain magnitude on the alleles function and demonstrate how surrounding residues orchestrate peptide specificity.
Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Trevor
T
Huyton
Heike
H
Schumacher
Rainer
R
Blasczyk
Christina
C
Bade-Doeding
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D057809:HEK293 Cells; D059948:HLA-B44 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D000596:Amino Acids; D059948:HLA-B44 Antigen; D010455:Peptides; D010649:Phenylalanine; D007930:Leucine