These interactions give MHC class I molecules a broad peptide-binding specificity. In addition, MHC molecules are highly polymorphic. As mentioned earlier, MHC genes are highly polymorphic and there are hundreds of different allelic variations of the MHC class I genes in the human population. Each individual carries only a small selection of these variants. The main differences between allelic MHC variants are found at certain sites in the peptide-binding cleft, resulting in different amino acids in key peptide-interaction sites. Because of this, different MHC variants preferentially bind different peptides. The peptides that can bind to a given MHC variant have the same or very similar amino acid residues at two or three particular positions along the peptide sequence. The amino acid side chains at these positions insert into pockets in the MHC molecule that are lined by the polymorphic amino acids. Because this binding anchors the peptide to the MHC molecule, the peptide residues involved are called the anchor residues, as illustrated in Fig. 4.21. Both the position and identity of these anchor residues can vary, depending on the particular MHC class I variant that is binding the peptide. However, most peptides that bind to MHC class I molecules have a hydrophobic (or sometimes basic) residue at the carboxy terminus that also serves to anchor the peptide in the groove. Whereas changing an anchor residue will in most cases prevent the peptide from binding, not every synthetic peptide of suitable length that
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Fig. 4.20 Peptides are bound to MHC class I molecules by their ends.
Mhc class i molecules interact with the backbone of a bound peptide (shown in yellow) through a series of hydrogen bonds and ionic interactions (shown as dotted blue lines) at each end of the peptide. The amino terminus of the peptide is to the left, the carboxy terminus to the right. Black circles are carbon atoms; red are oxygen; blue are nitrogen. The amino acid residues in the Mhc molecule that form these bonds are common to all Mhc class i molecules, and their side chains are shown in full (in gray) on a ribbon diagram of the Mhc class i groove. A cluster of tyrosine residues common to all Mhc class i molecules forms hydrogen bonds to the amino terminus of the bound peptide, while a second cluster of residues forms hydrogen bonds and ionic interactions with the peptide backbone at the carboxy terminus and with the carboxy terminus itself.
Fig. 4.21 Peptides bind to MHC molecules through structurally related anchor residues. Peptides eluted from two different Mhc class i molecules are shown in the upper and lower panels, respectively. The anchor residues (green) differ for peptides that bind different allelic variants of Mhc class i molecules but are similar for all peptides that bind to the same Mhc molecule. The anchor residues that bind a particular Mhc molecule need not be identical, but are always related: for example, phenylalanine (f) and tyrosine (Y) are both aromatic amino acids, whereas valine (V), leucine (L), and isoleucine (i) are all large hydrophobic amino acids. Peptides also bind to Mhc class i molecules through their amino (blue) and carboxy (red) termini.