Structural and evolutionary analysis of HLA-D-region products

Abstract

The major histocompatibility complex (MHC)—HLA in man and H–2 in mouse—encodes two classes of cell-surface antigens involved in the immune response. The amino acid sequences have been determined for a number of these molecules^1–11. Class I antigens, typified by the HLA–ABC antigens, are composed of a 43,000-molecular weight (MW) glycosylated transmembrane polypeptide with three external domains (α1, α2 and α3), of which the one nearest the membrane (α3) is associated with a 12,000-MW nonglycosylated poly peptide, β₂-microglobulin. The HLA-D-region or class II antigens, DR, DC and SB, are composed of two glycosylated transmembrane polypeptides, of MWs 34,000 (α-chain) and 28,000 (β-chain). Both chains have two external domains which presumably associate with each other, α2, β2 being membrane proximal and α1,β1 N-terminal and membrane distal. All four membrane-proximal domains (class I α3, β₂-microglobulin, class II α2 and β2) have amino acid sequences that show significant similarities with immunoglobulin constant-region domains^3,6,9,12,13. This, together with the similarly placed internal disulphide bonds, suggests they might have an immunoglobulin-like structure (Fig. 1). We have now used computer graphics techniques to predict a detailed three-dimensional structure for the membrane-proximal domains of the class II antigens (α2 and β2) based on the known coordinates of immunoglobulin constant domains (Fig. 2). The transmembrane regions of class II antigens have been modelled as two α-helices packed together. The proposed structure accounts for conservation of amino acids and leads to evolutionary predictions.