Class I MHC proteins

Figure 15.18 (a) Schematic representation of the path of the polypeptide chain in the structure of the class I MHC protein HLA-A2. Disulfide bonds are indicated as two connected spheres. The molecule is shown with the membrane proximal immunoglobulin-like domains (a3 and Pzm) at the bottom and the polymorphic al and a2 domains at the top. 

Figure 15.19 Schematic representation of the peptide-binding domain of a class I MHC protein. The al and a2 domains are viewed from the top of the molecule, showing the empty antigen-binding site as well as the surface that is contacted by a T-cell receptor. (Adapted from P.J. Bjdrkman et al.. Nature 329 506-512, 1987.)...

Class I MHC proteins occur in almost all nucleated cells. They mainly interact with cytotoxic T cells and are the reason for the rejection of transplanted organs. Class 1 MHC proteins are heterodimers (a 3). The p subunit is also known as P2-microglobulin. 

The illustration shows an interaction between a virus-infected body cell (bottom) and a CD8-carrying cytotoxic T lymphocyte (top). The infected cell breaks down viral proteins in its cytoplasm (1) and transports the peptide fragments into the endoplasmic reticulum with the help of a special transporter (TAP) (2). Newly synthesized class I MHC proteins on the endoplasmic reticulum are loaded with one of the peptides (3) and then transferred to the cell surface by vesicular transport (4). The viral peptides are bound on the surface of the a2 domain of the MHC protein in a depression formed by an insertion as a floor and two helices as walls (see smaller illustration). 

These proteins consist of a and /3 chains, (a) In class I MHC proteins, the small /3 chain is invariant but the amino acid sequence of the a chain exhibits a high degree of variability, localized in specific domains of the protein that appear on the outside of the cell. Each human produces up to six different a chains for class I MHC proteins, (b) In class II MHC proteins, both the a and /3 chains have regions of relatively high variability near their amino-terminal ends. 

Class II MHC proteins occur on the surfaces of a few types of specialized cells, including macrophages and B lymphocytes that take up foreign antigens. Like class I MHC proteins, the class II proteins are highly polymorphic, with many variants in the human popula-... 

F1GURE 5-22 Structure of a human class I MHC protein, (a) This model is derived in part from the known structure of the extracellular portion of the protein (PDB ID 1 DDH). The a chain of MHC is shown in gray the small /3 chain is blue the disulfide bonds are yellow. A bound ligand, a peptide derived from HIV, is shown in red. (b) Top view of the protein, showing a surface contour image of the site where peptides are bound and displayed. The HIV peptide (red) occupies the site. This part of the class I MHC protein interacts with T-cell receptors. 

The two classes of MHC proteins are displayed on different cell types. Class I MHC proteins are found on almost all nucleated cells, including killer T cells. Class II MHC proteins are found mainly on cells involved in the immune response, including antigen-presenting cells, B cells, and T helper cells, but not T killer cells. 

The three-dimensional structure of a large fragment of a human MHC class I protein, human leukocyte antigen A2 (HLA-A2), was solved in 1987 by Don Wiley and Pamela Bjorkman. Class I MHC proteins consist of a 44-kd a chain noncovalently bound to a 12-kd polypeptide called P " microglobulin. The a chain has three extracellular domains (a j,... 

The groove can be filled by a peptide from 8 to 10 residues long in an extended conformation. As we shall see (Section 33.5.6). MHC proteins are remarkably diverse in the human population each person expresses as many as six distinct class I MHC proteins and many different forms are present in different people. The first structure determined, HLA-A2, binds peptides that almost always have leucine in the second position and valine in the last position (Figure 33.25). Side chains from the MHC molecule interact with the amino and carboxyl termini and with the side chains in these two key positions. These residues are often referred to as the anchor residues. The other residues are highly variable. Thus, many millions of different peptides can be presented by this particular class I MHC protein the identities of only two of the nine residues are crucial for binding. Each class of MHC molecules requires a unique set of anchor residues. Thus, a tremendous range of peptides can be presented by these molecules. Note that one face of the bound peptide is exposed to solution where it can be examined by other molecules, particularly T-cell receptors. An additional remarkable feature of MHC-peptide complexes is their kinetic stability once bound, a peptide is not released, even over a period of days. 

Figure 33.22. Presentation of Peptides from Cytosolic Proteins. Class I MHC proteins on the surfaces of most cells display peptides that are derived from cytosolic proteins by proteolysis.

Figure 33.23. Class I MHC Protein. A protein of this class consists of two chains. The a chain begins with two domains that include a helices (a a 2), an immunoglobulin domain (a 3), a transmembrane domain, and a cytoplasmic tail. The second chain, (5 2" croglobulin, adopts an immunoglobulin fold.

Figure 33.25. Anchor Residues. (A) The amino acid sequences of three peptides that bind to the class I MHC protein HLA-A2 are shown. Each of these peptides has leucine in the second position and valine in the carboxyl-terminal position. (B) Comparison of the structures of these peptides reveals that the amino and carboxyl termini as well as the side chains of the leucine and valine residues are in essentially the same position in each peptide, whereas the remainder of the structures are quite different.

Figure 33.27. T-Cell Receptor Class I MHC Complex. The T-cell receptor binds to a class I MHC protein containing a bound peptide. The T-cell receptor contacts both the MHC protein and the peptide as shown by surfaces exposed when the complex is separated (right). These surfaces are colored according to the chain that they contact.

Figure 33.33. Class II MHC Protein. A class IIMHC protein consists of homologous a and P chains, each of which has an amino-terminal domain that constitutes half of the peptide-binding structure, as well as a carboxyl-terminal immunoglobulin domain. The peptide-binding site is similar to that in class I MHC proteins except that it is open at both ends, allowing class II MHC proteins to bind longer peptides than those bound by class I.

Figure 33.35. Variations on a Theme. (A) Cytotoxic T cells recognize foreign peptides presented in class I MHC proteins with the aid of the coreceptor CDS. (B) Helper T cells recognize peptides presented in class II MHC proteins by specialized antigen-presenting cells with the aid of the coreceptor CD4.

Figure 33.37. Polymorphism in Class I MHC Protein. The positions of sites with a high degree of polymorphism in the human population are displayed as red spheres on the structure of the amino-terminal part of a class I MHC... 

The groove can be filled by a peptide from 8 to 10 residues long in an extended conformation. As we shall see (p. 968), MHC proteins are remarkably diverse in the human population each person expresses as many as six distinct class I MHC proteins and many different forms are present in different people. The first structure determined, HLA-A2, binds peptides that almost always have leucine in the second position and valine in the last position (Figure 33.28). Side chains from the MHC molecule interact with the amino and carboxyl termini and with the side chains in these two key... 

Zhang, Q., and Salter, R. D. (1998). Distinct patterns of folding and interactions with calnexin and calreticulin in human class I MHC proteins with altered A-glycosylation. J. Immunol. 160, 831-837. 

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