Naturally processed peptides longer than nine amino acid residues bind to the class I MHC molecule HLA-A2.1 with high affinity and in different conformations.
An equilibrium binding assay was used to directly measure the relative affinities of naturally processed 9-mer, 10-mer, and 12-mer peptides for the human class I MHC molecule HLA-A2.1. The peptides exhibited a range of affinities with IC50 values of 11 to 214 nM. The mode of interaction between these peptides and HLA-A2.1 was examined using peptides in which Asp had been substituted for suspected anchor residues. Regardless of length, the previously identified Leu at position 2 relative to the amino terminus was critical for peptide binding. While the carboxyl terminal residue was also critical for the binding of a 9-mer peptide, it was much less important in the binding of longer peptides. Additional residues close to the carboxyl terminus that contained aliphatic hydrocarbon side chains were of similar or greater importance in peptide binding. In addition, residue at position 3 also appeared to be important for the binding of longer peptides. The data suggest that different naturally occurring longer peptides can bind in different conformations to class I MHC molecules. While one of these is similar to the kinked conformation described by others, another conformation would involve an extension of the carboxyl terminus out of the class I binding site. The ability of MHC molecules to accommodate the same peptide in different conformations would appear to have distinct advantages to the immune system.
Chen
Y
Y
Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville 22908.
Sidney
J
J
Southwood
S
S
Cox
A L
AL
Sakaguchi
K
K
Henderson
R A
RA
Appella
E
E
Hunt
D F
DF
Sette
A
A
Engelhard
V H
VH
D000595:Amino Acid Sequence; D001665:Binding Sites; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D015789:HLA-A2 Antigen; D009842:Oligopeptides