Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules.
The functional determinants of histocompatibility leukocyte antigen (HLA)-A2.1-peptide interactions have been detailed by the use of quantitative molecular binding assays and a chemically synthesized library of naturally occurring epitopes. The importance of hydrophobic anchor residues in position 2 and the C-terminus was confirmed. These anchors are necessary, but not sufficient, for high affinity binding, as the predictions based solely on these anchors are only about 30% accurate. Prominent roles for several other positions (1, 3, and 7) were also demonstrated. The location of these residues within the peptides matches secondary A2.1 pockets previously demonstrated by X-ray crystallography. From a functional standpoint, similar dominant negative effects on binding were observed for charged residues in both nonamers and decamers, while positive effects differed between nonamers and decamers. An extended motif taking into account secondary anchors increased the predictability of A2.1-binding epitopes to a level of 70%, underscoring the practical usefulness of extended motifs.
Ruppert
J
J
Cytel Corporation, San Diego, California 92121.
Sidney
J
J
Celis
E
E
Kubo
R T
RT
Grey
H M
HM
Sette
A
A
D000135:Acid Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D001665:Binding Sites; D002461:Cell Line, Transformed; D006678:HIV / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism; D006515:Hepatitis B virus / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology; D058950:Melanoma-Specific Antigens; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011467:Prostate / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
D000135:Acid Phosphatase; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins