HLA-E Allelic Variants

Abstract

Previous studies of HLA-E allelic polymorphism have indicated that balancing selection may be acting to maintain two major alleles in most populations, indicat-ing that a functional difference may exist between the alleles. The alleles differ at only one amino acid position, where an arginine at position 107 in HLA-E*0101 (E R) is replaced by a glycine in HLA-E*0103 (E G). To investigate possible functional differences, we have undertaken a study of the physical and biochemical properties of these two proteins. By comparing expression levels, we found that whereas steady-state protein levels were sim-ilar, the two alleles did in fact differ with respect to cell surface levels. To help explain this difference, we under-took studies of the relative differences in peptide affin-ity, complex stability, and three-dimensional structure between the alleles. The crystal structures for HLA-E G complexed with two distinct peptides were determined, and both were compared with the HLA-E R structure. No significant differences in the structure of HLA-E were induced as a result of binding different peptides or by the allelic substitution at position 107. However, there were clear differences in the relative affinity for peptide of each heavy chain, which correlated with and may be explained by differences between their thermal stabili-ties. These differences were completely consistent with the relative levels of the HLA-E alleles on the cell sur-face and may indeed correlate with functional differ-ences. This in turn may help explain the apparent bal-ancing selection acting on this locus.