The Nature of The
“Groovy” Peptide
The MHC groove, which binds
a single peptide, imposes some well‐defined restrictions on the nature and
length of the peptide that it can accommodate. However, at the majority of positions
in the peptide ligand, a surprising degree of redundancy is permitted and this
relates in part to residues interacting with the T‐cell receptor rather than
the MHC. Thus, each MHC molecule has the potential to bind hundreds or even
thousands of different peptide sequences so long as at certain amino acid
positions the peptides share characteristic conserved anchor residues for that
particular MHC allele. Different MHC alleles will bind a different range of
peptides thanks to the difference in sequence of the binding groove of the
different MHC variants.
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Figure 5.19 Binding of peptides to the MHC cleft. T‐cell receptor (TCR) “view” looking down on the α‐helices lining the cleft (see Figure 4.19b) represented in space‐filling models. (a) Peptide 309–317 from HIV‐1 reverse transcriptase
bound tightly within the class I HLA‐A2 cleft. In general, one to
four of the peptide side‐chains points towards the TCR, giving a
solvent accessibility of 17–27%. (b) Influenza hemagglutinin 306–318 lying in the class II HLA‐DR1 cleft. In contrast with class I, the peptide extends out of both ends
of the binding groove and from four to six side‐chains point towards the
TCR, increasing solvent accessibility to 35%. (Adapted from Vignali D.A.A. and
Strominger J.L. (1994) The Immunologist 2, 112. Reproduced with
permission of Hogrefe & er Publishers.)
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Binding to MHC class I
X‐ray crystallographic
analysis reveals the peptides to be tightly mounted along the length of the
groove in an extended configuration with no breathing space for α‐helical
structures (Figure 5.19). The molecular forces involved in peptide binding to MHC and in TCR
binding to peptide MHC are similar to those seen between antibody
and antigen (i.e., noncovalent).
The naturally occurring
peptides can be extracted from purified MHC class I and sequenced. They are
predominantly 8–10 residues long; because the MHC class I
peptide‐binding groove is closed at both ends, any peptides that are slightly
longer than this have to bulge upwards out of the cleft. Analysis of the peptide
pool sequences indicates amino acids with defined characteristics at certain
key positions (Table 5.1). These are called anchor positions and represent the
amino acid side‐chains required to fit into allele‐specific pockets in
the MHC groove (Figure 5.20a). There are usually two, sometimes three,
such major anchor positions for class I‐binding peptides, frequently at peptide
positions 2 (P2) and 9 (P9) but sometimes at other positions. For example,
the highly prevalent HLA‐A*0201 has a pocket that will accept leucine,
methionine, or isoleucine at peptide position P2 and a pocket that will accept
leucine, valine, isoleucine, or methionine at P9 (Table
5.1). In some HLA
alleles, instead of a major anchor pocket there are two or three more weakly
binding pockets. Even with the constraints of two or three anchor motifs, each
MHC class I allele can accommodate hundreds or even thousands of different
peptides. Thus, so long as the criteria for the anchor positions are met, the
other amino acids in the sequence can vary. Allele‐independent hydrogen‐bonding
to conserved residues at either end of the MHC class I groove occurs at the N‐
and C‐termini of the peptide.
Except in the case of
infection, the natural class I ligands will be self peptides derived from
proteins endogenously synthesized by the cell, histones, heat‐shock proteins,
enzymes, leader signal sequences, and so on. About 75% of these peptides
originate in the cytosol and most of them will be in low abundance, say 100–400
copies per cell. Thus proteins expressed with unusual abundance, such as
oncofetal proteins in tumors and viral antigens in infected cells, should be
readily detected by resting T‐cells.
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Figure 5.20 Allele‐specific pockets in the MHC‐binding grooves bind the major anchor residue motifs of the peptide
ligands. Cross‐section through the longitudinal axis of the
MHC groove. The two α‐helices forming the lateral walls of the groove lie horizontally above
and below the plane of the paper. (a) The class I groove is closed at both
ends. The anchor positions are very often at P2 and P9 but may also be at other
locations depending on the MHC allele (see Table 5.1). (b) By contrast, the
class II groove is open at both ends and does not constrain the length of the
peptide. There are usually three or four major anchor pockets with, for
example, P1 dominant for HLA‐DR1 and P4 dominant for HLA‐DR3.
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Binding to MHC class II
Unlike class I, the class II
groove is open at both ends and therefore can bind longer peptides, typically
about 15–20 amino acids long. However, just as for class I, it is
a stretch of about 9 amino acids that are directly involved in the interaction and this portion is referred to as the peptide binding
register. The other amino acids can extend from each end of the groove, quite
unlike the strait‐jacket of the class I ligand site (Figure
5.19 and Figure 5.20), and are susceptible to proteolytic trimming. With respect to class II
allele‐specific binding pockets for peptide side‐chains, the motifs are based
on three or four major anchor residues, typically but not invariably at P1, P4,
P6, and P9 (Figure 5.20b).
Unfortunately, it is
difficult to establish these preferences for the individual residues within a
given peptide. This is because although the length of the class II groove is
similar to that of class I, the open nature of the groove in class II places no
constraint on the length of the ligand. Thus, each class II molecule binds a
collection of peptides of varying length, and analysis of such a naturally
occurring pool isolated from the MHC would not establish which amino acid
side‐chains were binding preferentially to the nine available sites within the
groove. One approach to get around this problem is to study the binding of
soluble class II molecules to very large libraries of random‐sequence
nonapeptides expressed on the surface of bacteriophages.
Peptide binding leads to a
transition from a more open conformation to one with a more compact structure
extending throughout the peptide‐binding groove. The range of concentrations of
the different peptide complexes that result will engender a hierarchy of
dominance of epitopes with respect to their ability to interact with T‐cells.
