Fig. 4.22 Peptides bind to MHC class II molecules by interactions along the length of the binding groove. A peptide (yellow; shown as the peptide backbone only, with the amino terminus to the left and the carboxy terminus to the right) is bound by an Mhc class ii molecule through a series of hydrogen bonds (dotted blue lines) that are distributed along the length of the peptide. The hydrogen bonds toward the amino terminus of the peptide are made with the backbone of the Mhc class ii polypeptide chain, whereas throughout the peptide’s length bonds are made with residues that are highly conserved in Mhc class ii molecules. The side chains of these residues are shown in gray on the ribbon diagram of the Mhc class ii groove.
contains these anchor residues will bind the appropriate MHC class I molecule, and so the overall binding must also depend on the nature of the amino acids at other positions in the peptide. In some cases, particular amino acids are preferred in certain positions, whereas in others the presence of particular amino acids prevents binding. These additional amino acid positions are called ‘secondary anchors.’ These features of peptide binding enable an individual MHC class I molecule to bind a wide variety of different peptides, yet allow different MHC class I allelic variants to bind different sets of peptides. As we will see in Chapter 15, MHC polymorphisms also impact the binding of peptides derived from self-proteins and can influence the susceptibility of an individual to various autoimmune diseases.
4-16 The length of the peptides bound by MHC class II molecules is not constrained.
Like MHC class I molecules, MHC class II molecules that lack bound peptide are unstable. Peptide binding to MHC class II molecules has also been analyzed by elution of bound peptides and by X-ray crystallography, and differs in several ways from peptide binding to MHC class I molecules. Natural peptides that bind to MHC class II molecules are at least 13 amino acids long and can be much longer. The clusters of conserved residues that bind the two ends of a peptide in MHC class I molecules are not found in MHC class II molecules, and the ends of the peptide are not bound. Instead, the peptide lies in an extended conformation along the peptide-binding cleft. It is held there both by peptide side chains that protrude into shallow and deep pockets lined by polymorphic residues, and by interactions between the peptide backbone and the side chains of conserved amino acids that line the peptide-binding cleft in all MHC class II molecules (Fig. 4.22). Structural data show that amino acid side chains at residues 1, 4, 6, and 9 of an MHC class II-bound peptide can be held in these binding pockets.
The binding pockets of MHC class II molecules accommodate a greater variety of side chains than those of MHC class I molecules, making it more difficult to define anchor residues and to predict which peptides will be able to bind