Fig. 4.23 Peptides that bind MHC class II molecules are peptides can vary, and so by convention the first anchor residue variable in length and their anchor residues lie at various is denoted as residue 1. note that all of the peptides share a distances from the ends of the peptide. The sequences of a hydrophobic residue in position 1, a negatively charged residue set of peptides that bind to the mouse Mhc class ii Ak allele are [aspartic acid (D) or glutamic acid (e)] in position 4, and a tendency shown in the upper panel. All contain the same core sequence to have a basic residue [lysine (K), arginine (R), histidine (h), (shaded) but differ in length. in the lower panel, different peptides glutamine (Q), or asparagine (n)] in position 6 and a hydrophobic binding to the human Mhc class ii allele hLA-DR3 are shown. residue [for example, tyrosine (Y), leucine (L), phenylalanine (f)] in Anchor residues are shown as green circles. The lengths of these position 9.
a particular MHC class II variant (Fig. 4.23). Nevertheless, by comparing the sequences of known binding peptides it is usually possible to detect patterns of amino acids that permit binding to different MHC class II variants, and to model how the amino acids of this peptide sequence motif will interact with the amino acids of the peptide-binding cleft. Because the peptide is bound by its backbone and allowed to emerge from both ends of the binding groove, there is, in principle, no upper limit to the length of peptides that could bind to MHC class II molecules. An example of this is the protein known as invariant chain, part of which lies entirely across the peptide-binding groove of nascent MHC class II molecules during their synthesis in the endoplasmic reticulum. We will return in Chapter 6 to the role of the invariant chain in the loading of peptides onto MHC class II molecules. In most cases, long peptides bound to MHC class II molecules are trimmed by peptidases to a length of around 13–17 amino acids.
4-17 The crystal structures of several peptide:MHC:T-cell receptor complexes show a similar orientation of the T-cell receptor over the peptide:MHC complex.
At the time that the first X-ray crystallographic structure of a T-cell receptor was published, a structure of the same T-cell receptor bound to a peptide:MHC class I ligand was also produced. The orientation revealed by these structures showed that the T-cell receptor is aligned diagonally over the peptide and the peptide-binding cleft (Fig. 4.24). The TCRα chain lies over the α2 domain of the MHC molecule at the amino-terminal end of the bound peptide, as seen from the side view shown in Fig. 4.24a. The TCRβ chain lies over the MHC molecule’s α1 domain, closer to the carboxy-terminal end of the peptide. Figure 4.24b shows a view of this structure as if looking down through a transparent T-cell receptor to indicate where it contacts the MHC molecule. The CDR3 loops of both TCRα and TCRβ chains come together and lie over