forms are located in the peptide-binding cleft, influencing which peptides will bind and thus the specificity of the dual antigen presented to T cells. By contrast, β2-microglobulin, which does not contribute directly to peptide binding, is not polymorphic.
An MHC class II molecule consists of a noncovalent complex of two chains, α and β, both of which span the membrane (see Fig. 4.18). The MHC class II α chain is a different protein from the class I α chain. The MHC class II α and β chains are both encoded within the MHC. The crystallographic structure of the MHC class II molecule shows that it is folded very much like the MHC class I molecule, but the peptide-binding cleft is formed by two domains from different chains, the α1 and β1 domains. The major differences lie at the ends of the peptide-binding cleft, which are more open in MHC class II than in MHC class I molecules. Consequently, the ends of a peptide bound to an MHC class I molecule are substantially buried within the molecule, whereas the ends of peptides bound to MHC class II molecules are not. In both MHC class I and class II molecules, bound peptides are sandwiched between the two α-helical segments of the MHC molecule (Fig. 4.19). The T-cell receptor interacts with this compound ligand, making contacts with both the MHC molecule and the peptide antigen. As in the case of MHC class I molecules, the sites of major polymorphism in MHC class II molecules are located in the peptide-binding cleft.
Fig. 4.18 MHC class II molecules resemble MHC class I molecules in overall structure. The Mhc class ii molecule is composed of two transmembrane glycoprotein chains, α (34 kDa) and β (29 kDa), as shown schematically in panel d. each chain has two domains, and the two chains together form a compact four-domain structure similar to that of the Mhc class i molecule (compare with panel d of fig. 4.17). Panel a shows a computer graphic representation of the surface of the Mhc class ii molecule, in this case the human protein hLA-DR1, and panel b shows the equivalent ribbon diagram. n, amino terminus; c, carboxy terminus. The α2 and β2 domains, like the α3 and β2-microglobulin domains of the Mhc class i molecule, have amino acid sequence and structural similarities to immunoglobulin c domains; in the Mhc class ii molecule the two domains forming the peptide-binding cleft are contributed by different chains and are therefore not joined by a covalent bond (see panels c and d). Another important difference, not apparent in this diagram, is that the peptide-binding groove of the Mhc class ii molecule is open at both ends.
Fig. 4.19 MHC molecules bind peptides tightly within the cleft. When Mhc molecules are crystallized with a single synthetic peptide antigen, the details of peptide binding are revealed. in Mhc class i molecules (panels a and c), the peptide is bound in an elongated conformation with both ends tightly bound at either end of the cleft. in Mhc class ii molecules (panels b and d), the peptide is also bound in an elongated conformation but the ends of the peptide are not tightly bound and the peptide extends beyond the cleft. The upper surface of the peptide:Mhc complex is recognized by T cells, and is composed of residues of the Mhc molecule and the peptide. The amino acid side chains of the peptide insert into pockets in the peptide-binding groove of the Mhc molecule; these pockets are lined with residues that are polymorphic within the Mhc. in representations c and d, the surfaces of the different pockets for the different amino acids are depicted as areas of different colors. Structures courtesy of