Peptide Binding to MHC Class I and II

In the cellular immune response, peptides are displayed to T cells in complex with class I or class II MHC molecules. Both classes of MHC are heterodimers of similar structures; they are composed of three domains, two Ig-like and one a/p domain (MHC fold) that forms the peptide binding site.

Whereas in class I MHC molecules, the peptide binding site is constructed from the heavy chain only, in class II MHC, it is formed by both chains. A P-pleated sheet forms the floor of the binding groove, which is flanked by a-helices (Fig. 2). Polymorphic residues in the a-helices and P-sheet floor cluster at the center of the binding groove and change its shape and chemical properties, thus accounting for the peptide-specific motifs that have been identified for each MHC allele [1-3].

Class I MHC molecules bind peptides in an extended conformation with the C terminus and the other main anchor residues buried in allele-specific pockets, leaving the upward-pointing peptide side chains available for direct interaction with the TCRs. Thus, the peptide lengths are usually 8 to 10 residues [4,5]; substantially longer peptides can bind but, due to the fixing of their N and C termini, they must bulge out of the binding groove [6].

In class II MHC, the peptide termini are not fixed, and the bound peptides can be significantly longer than in class I MHC; the peptide backbone is confined to repeating polypro-line type II, helical, ribbon-like conformations [7]. The pep-tides also lie slightly deeper in the binding groove. Thus, the peptide has the potential to dominate the TCR/pMHC interface more in class I due to the ability to bulge out of the groove depending on the length of the peptide and the pMHC [6]. Additionally, extensive ridges in some MHCs force the pep-tide to bulge even higher out of the groove and provide more intimate contact with the TCR [8,9].

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