Variability and conformation of HLA class I antigens: a predictive approach to the spatial arrangement of polymorphic regions

Abstract

Comparison of available sequences of HLA-A and HLA-B antigens shows that variable positions are predominantly localized in 4 segments spanning residues 63-85 105-116, 138-156 and 177-194. The 4th segment is unique in that it contains no differences between antigens of the same locus. Secondary folding of HLA H chain was estimated by 3 independent predictive methods and areas of defined structure were correlated with the distribution of local hydrophobicity to outline putative internal and external portions. The 3 analyses each independently predict a high probability for .beta. structure in the .alpha.1, .alpha.2 and .alpha.3 domains. A single .alpha.-helix is predicted within residues 146-160, a segment of likely importance in cytotoxic T cell recognition and graft rejection. Substitutions within this segment are spatially related by the helical turn. Variable residues usually lie in areas of high local hydrophilicity, and therefore they are probably on the surface of the molecule. The model predicts that they are frequently located in .beta. strands, .beta.-turns or the .alpha.-helix, so that most substitutions would be accommodated within rigid frameworks that may impose structural constraints to variability. The secondary structure of .alpha.1, .alpha.2 and .alpha.3 domains presents some analogies that suggest that they might share common features in their tertiary folding. The predicted structure of .alpha.3 is strongly reminiscent of that of Ig constant domains. Possible arrangements of elements of secondary structure are discussed, as an attempt to situating the polymorphic regions of HLA class I antigens in a spatial context.