Peptide binding

Class I MHC molecules bind to peptides usually of 8 or 9 residues in length. The binding specificity is broad: many different peptides bind to a given class I MHC molecule, although there are clear preferences depending on the peptide sequence, and these vary among class I molecules of a given genotype. Binding of peptides to class I MHC molecules has been studied using purified molecules in solution but most frequently using cells deficient in TAP transporters. These cells have poor basal expression of class I MHC molecules but will increase this expression when cultured with peptides.

In common with the class II molecule, class I molecules do not discriminate between foreign and self peptides. Peptides have been extracted from class I

molecules of different target cells. These peptides were isolated, fractionated, usually by reverse phase high-pressure liquid chromatography, and then sequenced. Class I molecules were found to contain hundreds of peptides, many of them representing autologous cytosolic proteins.

The biochemical basis of peptide binding has been extensively analyzed following the pioneering studies by Bjorkman and colleagues from Wiley and Strom-inger's laboratories. There are features in common between the structure of the binding site of both class I and II molecules. The binding site is located at the top of the molecule. It contains a cleft or 'groove', the peptide-combining site, which is made by a platform of (3-pleated sheet surrounded by two helices. The groove is about 30 A in length and 12 A in its center. Amino acid residues responsible for the extensive allelic polymorphism contact the peptides and are responsible for their binding specificity. For class I MHC molecules, both the a, and a> domains contribute to the combining site. Each domain contributes to half the number of (3 sheets and one of the helices. The a? domain of the heavy chain and [^-microglobulin serve to hold and give support to the top two domains.

Peptides are bound to class I molecules as a result of two sets of interaction. One is that of conserved amino acid residues of the class I heavy chain, with amino acids at each end of the peptide. Amino acid residues at the ends of the peptide form extensive hydrogen bonds with conserved residues at subsites located at each end (termed pockets A and F). The peptides bound at each end will run through the groove as an extended conformation. Depending on the particular peptide and class I molecule, the peptide may or may not bulge or kink towards the middle of it. The extensive hydrogen bonding of the main chain atoms of the peptide with the conserved residues of the MHC molecule stabilizes the complex. A second set of interactions takes place with side-chains of the peptide. These side-chain-specific interactions are responsible for the sequence binding motifs that have been identified. Particularly prominent for most class I bound peptides are interactions at the second and last residue.

Some of the residues in the peptide are solvent exposed and will establish contact with the T cell receptor. The X-ray structure of the T cell receptor bound to a class I MHC molecule shows the receptor contacting the a helices of the MHC molecules as well as the peptide. The peptide occupies about the center of the peptide-binding structure available to the T cell. The receptor is oriented slightly diagonal to the main axis of the peptide, with the CDR3 region of their a and 3 chains contacting the middle of the peptides and the CDR1 and CDR2 contacting the peptide ends and the MHC. Thus the structural analysis confirms the dual specificity of the T cell receptor for peptide and MHC molecules, as was predicted by the findings of MHC restriction.

See also: Adhesion molecules; Antigen-presenting cells; Antigen presentation via MHC class II molecules; MHC peptide-binding specificity; CD8; Cytotoxic T lymphocytes; H2 class I; HLA class I; Interferon 7; MHC, evolution of; MHC, functions of; MHC restriction; T cell receptor, recognition by.

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