MHC class I molecules (see Fig. 4.17) consist of two polypeptide chains. One chain, the α chain, is encoded in the MHC (on chromosome 6 in humans) and is noncovalently associated with a smaller chain, β2-microglobulin, which is encoded on a different chromosome—chromosome 15 in humans. Only the class I α chain spans the membrane. The complete MHC class I molecule has four domains, three formed from the MHC-encoded α chain, and one contributed by β2-microglobulin. The α3 domain and β2-microglobulin closely resemble Ig-like domains in their folded structure. The folded α1 and α2
Fig. 4.16 Differences in the recognition of hen egg-white lysozyme by immunoglobulins and T-cell receptors. Antibodies can be shown by X-ray crystallography to bind epitopes on the surface of proteins, as shown in panel a, where the epitopes for three antibodies are shown in different colors on the surface of hen egg-white lysozyme (see also fig. 4.10). in contrast, the epitopes recognized by T-cell receptors need not lie on the surface of the molecule, because the T-cell receptor recognizes not the antigenic protein itself but a peptide fragment of the protein. The peptides corresponding to two T-cell epitopes of lysozyme are shown in panel b. one epitope, shown in blue, lies on the surface of the protein, but a second, shown in red, lies mostly within the core and is inaccessible in the folded protein. This implies that T-cell receptors do not recognize their epitopes in the context of the native protein. Panel a courtesy of S. Sheriff.
domains form the walls of a cleft on the surface of the molecule; because this is where the peptide binds, this part of the MHC molecule is known as the peptide-binding cleft or peptide-binding groove. The MHC molecules are highly polymorphic, and the major differences between the different allelic
Fig. 4.17 The structure of an MHC class I molecule determined by X-ray crystallography. Panel a shows a computer graphic representation of a human Mhc class i molecule, hLA-A2, which has been cleaved from the cell surface by the enzyme papain. The surface of the molecule is shown, colored according to the domains shown in panels b–d and described below. Panels b and c show a ribbon diagram of that structure. Shown schematically in panel d, the Mhc class i molecule is a heterodimer of a membrane-spanning α chain (molecular weight 43 kDa) bound noncovalently to β2-microglobulin (12 kDa), which does not span the membrane. The α chain folds into three domains: α1, α2, and α3. The α3 domain and β2-microglobulin show similarities in amino acid sequence to immunoglobulin c domains and have similar folded structures, whereas the α1 and α2 domains are part of the same polypeptide and fold together into a single structure consisting of two separated α helices lying on a sheet of eight antiparallel β strands. The folding of the α1 and α2 domains creates a long cleft or groove, which is the site at which peptide antigens bind to the Mhc molecules. for class i molecules, this groove is open at only one end. The transmembrane region and the short stretch of peptide that connects the external domains to the cell surface are not seen in panels a and b because they have been removed by the digestion with papain. As can be seen in panel c, looking down on the molecule from above, the sides of the cleft are formed from the inner faces of the two α helices; the β pleated sheet formed by the pairing of the α1 and α2 domains creates the floor of the cleft.