7
Introduction
How are peptides presented by MHC II molecules?
As MHC molecules have to present peptides with various sequences arising from a
wide range of different pathogens their binding patterns have to be quite distinct from
receptors which bind only one specific peptide. Thus, on the one hand the binding
groove has to target common peptide features to accommodate different peptides and on
the other hand has to build tight and specific interactions to form a long-lasting
individual complex. Therefore, peptides are bound in an elongated orientation enabled
by two major interactions between peptide and MHC molecule.
First, a set of conserved hydrogen bonds between residues of the MHC molecule and
the peptide backbone fix the peptide along the groove. In the case of MHC
II molecules,
conserved amino acids of the α1 (Phe51, Ser53, Asn62, Asn69 and Arg76) and ß1
domain (Trp61, His81 and Asn82) form 12 hydrogen bonds to the peptide backbone
which are located close to the peptide N-terminus (6), the middle part of the peptide (2)
and the peptide C-terminus (4) (figure 1.4, B). The second main contribution to peptide-
binding and alignment is the tight interaction of peptide residues with shallow and deep
pockets formed by MHC molecules (figure 1.4, A, C). Peptide residues protrude into
these pockets and are partially or entirely covered by residues of the MHC molecule.
Peptide residues residing in deep pockets are particularly important as they provide
anchor points for the peptide along the binding groove. For MHC I and MHC II
molecules the binding pockets are located at fixed positions of the binding cleft.
Therefore, for efficient binding peptides have to contain anchor residues at consistent
positions. For MHC II molecules the binding pockets are at positions P1, P4, P6, and P9
(figure 1.4, D).
As the amino acids which form the binding pockets are highly polymorphic, the
cavity size can vary between different MHC alleles. This divergence results in binding
preference of MHC molecules for different peptides. In contrast MHC residues which
form the hydrogen bond network between peptide and MHC molecules are highly
conserved and as they interact with peptide backbone and not peptide side chains, these
interactions target most peptides equally.
The peptide is an integral part of the MHC molecule as it stabilizes the structure. In
the absence of bound peptide or chaperones, MHC I and MHC II molecules readily
aggregate. This ensures that only stable MHC/peptide complexes are transported to the
cell surface and MHC molecules present peptides that were processed within the cell.