Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.
HLA-DR13 has been associated with resistance to two major infectious diseases of humans. To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position. The eluted peptides were subjected to pool sequencing or individual peptide sequencing by tandem MS or Edman microsequencing. Sequences were obtained for 23 peptides from nine source proteins. Three pool sequences for each allele and the sequences of individual peptides were used to define binding motifs for each allele. Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301. Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1*1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly-->Val change at position 86. These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.
Davenport
M P
MP
Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
Quinn
C L
CL
Chicz
R M
RM
Green
B N
BN
Willis
A C
AC
Lane
W S
WS
Bell
J I
JI
Hill
A V
AV
D000483:Alleles; D000595:Amino Acid Sequence; D001402:B-Lymphocytes; D002461:Cell Line, Transformed; D004198:Disease Susceptibility / Q000276:immunology; D008401:Gas Chromatography-Mass Spectrometry; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification; D017386:Sequence Homology, Amino Acid
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D046911:Macromolecular Substances; D010446:Peptide Fragments