R.L. Stanfield and i.A. Wilson.
4-14 Peptides are stably bound to MHC molecules, and also serve to stabilize the MHC molecule on the cell surface.
An individual can be infected by a wide variety of pathogens, whose proteins will not generally have peptide sequences in common. For T cells to be able to detect the widest possible array of infections, the MHC molecules (both class I and class II) of an individual should be able to bind stably to many different peptides. This behavior is quite distinct from that of other peptide-binding receptors, such as those for peptide hormones, which usually bind only a single type of peptide. The crystal structures of peptide:MHC complexes have helped to show how a single binding site can bind a peptide with high affinity while retaining the ability to bind a wide variety of different peptides.
An important feature of the binding of peptides to MHC molecules is that the peptide is bound as an integral part of the MHC molecule’s structure, and MHC molecules are unstable when peptides are not bound. This dependence on bound peptide applies to both MHC class I and MHC class II molecules. Stable peptide binding is important, because otherwise peptide exchanges occurring at the cell surface would prevent peptide:MHC complexes from being reliable indicators of infection or of uptake of a specific antigen. When MHC molecules are purified from cells, their stably bound peptides co-purify with them, and this fact has enabled the peptides bound by particular MHC molecules to be analyzed. Peptides are released from the MHC molecules by denaturing the complex in acid, and they are then purified and sequenced. Pure synthetic peptides can also be incorporated into empty MHC molecules and the structure of the complex determined, revealing details of the contacts between the MHC molecule and the peptide. From such studies a detailed picture of the binding interactions has been built up. We first discuss the peptide-binding properties of MHC class I molecules.
4-15 MHC class I molecules bind short peptides of 8–10 amino acids by both ends.
Binding of a peptide to an MHC class I molecule is stabilized at both ends of the peptide-binding cleft by contacts between atoms in the free amino and carboxy termini of the peptide and invariant sites that are found at each end of the cleft in all MHC class I molecules (Fig. 4.20). These are thought to be the main stabilizing contacts for peptide:MHC class I complexes, because synthetic peptide analogs lacking terminal amino and carboxyl groups fail to bind stably to MHC class I molecules. Other residues in the peptide serve as additional anchors. Peptides that bind to MHC class I molecules are usually 8–10 amino acids long. Longer peptides are thought to bind, however, particularly if they can bind at their carboxy terminus, but they are subsequently shortened to 8–10 amino acids through cleavage by exopeptidases present in the endoplasmic reticulum, which is where MHC class I molecules bind peptides. The peptide lies in an elongated conformation along the cleft; variations in peptide length seem to be accommodated, in most cases, by a kinking in the peptide backbone. However, in some cases, length variation can also be accommodated in MHC class I molecules by allowing the peptide to extend out of the cleft at the carboxy terminus.