A single amino-acid polymorphism in pocket A of HLA-A*6602 alters the auxiliary anchors compared with HLA-A*6601 ligands.
In this study we have sequenced peptides eluted from a truncated recombinant HLA-A*6602 molecule, and compared their features with data reported for peptides presented in the A*6601 molecule. A striking change in the amino-acid binding preferences was observed at peptide position P1, which interacts with pocket A of the HLA peptide-binding region. For A*6601, aspartic acid and glutamic acid, both of which possess polar acidic side-chains, have been described as auxiliary anchors. This is in marked contrast to A*6602, where we observed serine, which has a neutral polar side-chain, as auxiliary anchor at P1. Accordingly, this shift in the physico-chemical properties of the auxiliary anchor may be best explained by the HLA amino-acid polymorphism at position 163, where arginine (hydrophilic, alkaline) in A*6601 has been replaced by glutamic acid in A*6602. This amino-acid exchange results in a shift towards higher acidity in pocket A, apparently resulting in the loss of preference for acidic auxiliary anchors, and leading to the preference for the neutral amino acid serine. The change of the auxiliary anchor residue at P1 is likely to alter the spectrum of peptides presented by A*6602 compared with A*6601, which may result in allogenicity in the case of a mismatch in allogeneic stem cell transplantation.
Bade-Doeding
Christina
C
Department of Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
Elsner
Holger-Andreas
HA
Eiz-Vesper
Britta
B
Seltsam
Axel
A
Holtkamp
Ute
U
Blasczyk
Rainer
R
D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D002846:Chromatography, Affinity; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D015234:HLA-A Antigens; D008024:Ligands; D010446:Peptide Fragments; D011994:Recombinant Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D012694:Serine; D001120:Arginine