Alpha-2 domain polymorphism and HLA class I peptide loading.
Diversity within the class I HLA antigen binding groove is positioned to moderate the presentation of peptide ligands. Polymorphism is widely dispersed about the peptide binding groove, and unravelling the functional significance of a given polymorphism requires comparative analysis of peptides presented by class I subtypes differing at the position(s) in question. Previous studies have demonstrated that not all class I polymorphisms act equally, and to determine the impact of substitutions specifically located in the alpha2 domain, peptides purified from B*1501, B*1512, B*1510, and B*1518 were examined by pooled Edman sequencing and comparative mass spectrometric analysis. Molecule B*1512 differs from B*1501 at residues 166 (Glu to Asp) and 167 (Trp to Gly) of the alpha2 domain. The pooled motif and ion mass ligand maps for B*1512 tightly matched those of B*1501, demonstrating that the 166/167 polymorphism between B*1501 and B*1512 has little impact upon ligand presentation. Although the 166/167 polymorphism minimally affects peptide binding preferences, this polymorphism makes B*1512 and B*1501 quite distinct by serology. We then compared the B70 molecules B*1510 and B*1518. The two are almost indistinguishable by serology and differ only by an alpha2 polymorphism at 116. Comparative peptide mapping shows that a Tyr to Ser polymorphism at 116 drastically changes the ligands bound by B*1510 and B*1518; no overlaps could be found. Polymorphisms in alpha2 therefore vary from subtle to extreme in the manner by which they moderate ligand presentation, and serologic crossreactivity did not reflect the ligands presented by these B15 subtypes.
Prilliman
K R
KR
Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
Crawford
D
D
Hickman
H D
HD
Jackson
K W
KW
Wang
J
J
Hildebrand
W H
WH
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein; D013329:Structure-Activity Relationship; D014162:Transfection
D015235:HLA-B Antigens; D008024:Ligands