Class I and II Molecules Exhibit Polymorphism in the Region That Binds to Peptides

Several hundred different allelic variants of class I and II MHC molecules have been identified in humans. Any one individual, however, expresses only a small number of these molecules— up to 6 different class I molecules and up to 12 different class II molecules. Yet this limited number of MHC molecules must be able to present an enormous array of different antigenic pep-tides to T cells, permitting the immune system to respond specifically to a wide variety of antigenic challenges. Thus, pep-tide binding by class I and II molecules does not exhibit the fine specificity characteristic of antigen binding by antibodies and T-cell receptors. Instead, a given MHC molecule can bind

Peptide binding by class I and class II MHC molecules

Class I molecules

Class II molecules

Peptide-binding domain

Nature of peptide-binding cleft

General size of bound peptides

Peptide motifs involved in binding to MHC molecule

Nature of bound peptide al /a2

Closed at both ends

8-10 amino acids

Anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor

Extended structure in which both ends interact with MHC cleft but middle arches up away from MHC molecule al /pi

Open at both ends

13-18 amino acids

Anchor residues distributed along the length of the peptide

Extended structure that is held at a constant elevation above the floor of MHC cleft numerous different peptides, and some peptides can bind to several different MHC molecules. Because of this broad specificity, the binding between a peptide and an MHC molecule is often referred to as "promiscuous."

Given the similarities in the structure of the peptide-bind-ing cleft in class I and II MHC molecules, it is not surprising that they exhibit some common peptide-binding features (Table 7-2). In both types of MHC molecules, peptide lig-ands are held in a largely extended conformation that runs the length of the cleft. The peptide-binding cleft in class I molecules is blocked at both ends, whereas the cleft is open in class II molecules (Figure 7-10). As a result of this difference, class I molecules bind peptides that typically contain 8-10 amino acid residues, while the open groove of class II molecules accommodates slightly longer peptides of 13-18 amino acids. Another difference, explained in more detail below, is that class I binding requires that the peptide contain specific amino acid residues near the N and C termini; there is no such requirement for class II peptide binding.

The peptide-MHC molecule association is very stable (Kd ~ 10~6) under physiologic conditions; thus, most of the MHC molecules expressed on the membrane of a cell will be associated with a peptide of self or nonself origin.

CLASS I MHC-PEPTIDE INTERACTION

Class I MHC molecules bind peptides and present them to CD8+ T cells. In general, these peptides are derived from endogenous intracellular proteins that are digested in the cy-tosol. The peptides are then transported from the cytosol into the cisternae of the endoplasmic reticulum, where they interact with class I MHC molecules. This process, known as the cytosolic or endogenous processing pathway, is discussed in detail in the next chapter.

Each type of class I MHC molecule (K, D, and L in mice or A, B, and C in humans) binds a unique set of peptides. In addition, each allelic variant of a class I MHC molecule (e.g., H-2Kk and H-2Kd) also binds a distinct set of peptides. Because a single nucleated cell expresses about 105 copies of each class I molecule, many different peptides will be expressed simultaneously on the surface of a nucleated cell by class I MHC molecules.

Class Mhc Space Filling

FIGURE 7-10

| MHC class I and class II molecules with bound peptides. (a) Space-filling model of human class I molecule HLA-A2 (white) with peptide (red) from HIV reverse transcriptase (amino acid residues 309-317) in the binding groove. ^-microglobulin is shown in blue. Residues above the peptide are from the al domain, those below from a2. (b) Space-filling model of human class II molecules HLA-DR1 with the DRa chain shown in white and the DRp chain in blue. The peptide (red) in the binding groove is from influenza hemagglutinin (amino acid residues 306-318). [From D. A. Vignali and J. Strominger, 1994, The Immunologist 2:112.]

FIGURE 7-10

| MHC class I and class II molecules with bound peptides. (a) Space-filling model of human class I molecule HLA-A2 (white) with peptide (red) from HIV reverse transcriptase (amino acid residues 309-317) in the binding groove. ^-microglobulin is shown in blue. Residues above the peptide are from the al domain, those below from a2. (b) Space-filling model of human class II molecules HLA-DR1 with the DRa chain shown in white and the DRp chain in blue. The peptide (red) in the binding groove is from influenza hemagglutinin (amino acid residues 306-318). [From D. A. Vignali and J. Strominger, 1994, The Immunologist 2:112.]

In a critical study of peptide binding by MHC molecules, peptides bound by two allelic variants of a class I MHC molecule were released chemically and analyzed by HPLC mass spectrometry. More than 2000 distinct peptides were found among the peptide ligands released from these two class I MHC molecules. Since there are approximately 105 copies of each class I allelic variant per cell, it is estimated that each of the 2000 distinct peptides is presented with a frequency of 100-4000 copies per cell. Evidence suggests that as few as 100 peptide-MHC complexes are sufficient to target a cell for recognition and lysis by a cytotoxic T lymphocyte with a receptor specific for this target structure.

The bound peptides isolated from different class I molecules have been found to have two distinguishing features: they are eight to ten amino acids in length, most commonly nine, and they contain specific amino acid residues that appear to be essential for binding to a particular MHC molecule. Binding studies have shown that nonameric peptides bind to class I molecules with a 100- to 1000-fold higher affinity than do peptides that are either longer or shorter, suggesting that this peptide length is most compatible with the closed-ended peptide-binding cleft in class I molecules. The ability of an individual class I MHC molecule to bind to a diverse spectrum of peptides is due to the presence of the same or similar amino acid residues at several defined positions along the peptides (Figure 7-11). Because these amino acid residues anchor the peptide into the groove of the MHC molecule, they are called anchor residues. The side chains of the anchor residues in the peptide are complementary with surface features of the binding cleft of the class I MHC molecule. The amino acid residues lining the binding sites vary among different class I allelic variants and

123456789

Eluted from

H-2Kd

A

= alanine

K =

lysine

R =

arginine

E

= glutamic acid

L =

leucine

S =

serine

F

= phenylalanine

N =

asparagine

T =

threonine

G

= glycine

P =

proline

V =

valine

H

= histidine

Q =

glutamine

Y =

tyrosine

I

= isoleucine

Examples of anchor residues (blue) in nonameric peptides eluted from two class I MHC molecules. Anchor residues that interact with the class I MHC molecule tend to be hydrophobic amino acids. [Datafrom V. H. Engelhard, 1994, Curr. Opin. Immunol. 6:13.]

FIGURE 7-11

Examples of anchor residues (blue) in nonameric peptides eluted from two class I MHC molecules. Anchor residues that interact with the class I MHC molecule tend to be hydrophobic amino acids. [Datafrom V. H. Engelhard, 1994, Curr. Opin. Immunol. 6:13.]

determine the identity of the anchor residues that can interact with the molecule.

All peptides examined to date that bind to class I molecules contain a carboxyl-terminal anchor. These anchors are generally hydrophobic residues (e.g., leucine, isoleucine), although a few charged amino acids have been reported. Besides the anchor residue found at the carboxyl terminus, another anchor is often found at the second or second and third positions at the amino-terminal end of the peptide (see Figure 7-11). In general, any peptide of correct length that contains the same or similar anchor residues will bind to the same class I MHC molecule. The discovery of conserved anchor residues in peptides that bind to various class I MHC molecules may permit prediction of which peptides in a complex antigen will bind to a particular MHC molecule, based on the presence or absence of these motifs.

X-ray crystallographic analyses of peptide-class I MHC complexes have revealed how the peptide-binding cleft in a given MHC molecule can interact stably with a broad spectrum of different peptides. The anchor residues at both ends of the peptide are buried within the binding cleft, thereby holding the peptide firmly in place (Figure 7-12). As noted already, nonameric peptides are bound preferentially; the main contacts between class I MHC molecules and peptides involve residue 2 at the amino-terminal end and residue 9 at the carboxyl terminus of the nonameric peptide. Between the anchors the peptide arches away from the floor of the cleft in the middle (Figure 7-13), allowing peptides that are slightly longer or shorter to be accommodated. Amino acids that arch away from the MHC molecule are more exposed and presumably can interact more directly with the T-cell receptor.

CLASS II MHC-PEPTIDE INTERACTION

Class II MHC molecules bind peptides and present these peptides to CD4+ T cells. Like class I molecules, molecules of class II can bind a variety of peptides. In general, these pep-tides are derived from exogenous proteins (either self or nonself), which are degraded within the endocytic processing pathway (see Chapter 8). Most of the peptides associated with class II MHC molecules are derived from membrane-bound proteins or proteins associated with the vesicles of the endocytic processing pathway. The membrane-bound proteins presumably are internalized by phagocytosis or by receptor-mediated endocytosis and enter the endocytic processing pathway at this point. For instance, peptides derived from digestion of membrane-bound class I MHC molecules often are bound to class II MHC molecules.

Peptides recovered from class II MHC-peptide complexes generally contain 13-18 amino acid residues, somewhat longer than the nonameric peptides that most commonly bind to class I molecules. The peptide-binding cleft in class II molecules is open at both ends (see Figure 7-10b), allowing longer peptides to extend beyond the ends, like a long hot dog in a bun. Peptides bound to class II MHC molecules maintain a roughly constant elevation on the

FIGURE 7-12

Model of the solvent-accessible area of class I H-2Kb, depicting the complex formed with a vesicular stomatitis virus (VSV-8) peptide (left, yellow backbone) and Sendai virus (SEV-9) nucleo-protein (right, blue backbone). Water molecules (blue spheres) interact with the bound peptides. The majority of the surface of both peptides is inaccessible for direct contact with T cells (VSV-8 is 83% buried; SEV-9 is 75% buried). The H-2Kb surface in the two complexes exhibits a small, but potentially significant, conformational variation, especially in the central region of the binding cleft on the right side of the peptides, which corresponds to the a helix in the a2 domain (see Figure 7-6b). [From M. Motsumuro et ol., 1992, Science 257:927; photogrophs courtesy of D. H. Fremont, M. Motsumuro, M. Pique, ond I. A. Wotson.]

FIGURE 7-12

Model of the solvent-accessible area of class I H-2Kb, depicting the complex formed with a vesicular stomatitis virus (VSV-8) peptide (left, yellow backbone) and Sendai virus (SEV-9) nucleo-protein (right, blue backbone). Water molecules (blue spheres) interact with the bound peptides. The majority of the surface of both peptides is inaccessible for direct contact with T cells (VSV-8 is 83% buried; SEV-9 is 75% buried). The H-2Kb surface in the two complexes exhibits a small, but potentially significant, conformational variation, especially in the central region of the binding cleft on the right side of the peptides, which corresponds to the a helix in the a2 domain (see Figure 7-6b). [From M. Motsumuro et ol., 1992, Science 257:927; photogrophs courtesy of D. H. Fremont, M. Motsumuro, M. Pique, ond I. A. Wotson.]

floor of the binding cleft, another feature that distinguishes peptide binding to class I and class II molecules.

Peptide binding studies and structural data for class II molecules indicate that a central core of 13 amino acids determines the ability of a peptide to bind class II. Longer peptides may be accommodated within the class II cleft, but the binding characteristics are determined by the central 13 residues. The peptides that bind to a particular class II molecule often have internal conserved "motifs," but unlike class I-binding peptides, they lack conserved anchor residues. Instead, hydrogen bonds between the backbone of the peptide and the class II molecule are distributed throughout the binding site rather than being clustered predominantly at the ends of the site as for class I-bound peptides. Peptides that bind to class II MHC molecules contain an internal sequence comprising 7-10 amino acids that provide the major contact points. Generally, this sequence has an aromatic or hydrophobic residue at the amino terminus and three additional hydrophobic residues in the middle portion and carboxyl-terminal end of the peptide.

In addition, over 30% of the peptides eluted from class II molecules contain a proline residue at position 2 and another cluster of prolines at the carboxyl-terminal end.

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  • Kristian
    What is a main distinguishing feature of both the MHC Class I and Class II molecules?
    8 years ago

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