Fig. 4.26 The structures of the CD4 and CD8 co-receptor molecules. The cD4 molecule contains four ig-like domains, shown in schematic form in panel a and as a ribbon diagram from the crystal structure in panel b. The amino-terminal domain, D1, is similar in structure to an immunoglobulin V domain. The second domain, D2, although related to an immunoglobulin domain, is different from both V and c domains and has been termed a c2 domain. The first two domains of cD4 form a rigid rodlike structure that is linked to the two carboxy-terminal domains by a flexible link. The binding site for Mhc class ii molecules involves mainly the D1 domain. The cD8 molecule is a heterodimer of an α and a β chain covalently linked by a disulfide bond. An alternative form of cD8 exists as a homodimer of α chains. The heterodimer is depicted in panel a, whereas the ribbon diagram in panel b is of the homodimer. cD8α and cD8β chains have very similar structures, each having a single domain resembling an immunoglobulin V domain and a stretch of polypeptide chain, believed to be in a relatively extended conformation, that anchors the V-like domain to the cell membrane.
rod about 6 nm long, which is joined by a flexible hinge to a similar rod formed by the third and fourth domains (D3 and D4). The MHC-binding region on CD4 is located mainly on a lateral face of the D1 domain, and CD4 binds to a hydrophobic crevice formed at the junction of the α2 and β2 domains of the MHC class II molecule (Fig. 4.27a). This site is well away from the site where the T-cell receptor binds, as shown by the complete crystal structure of a T-cell receptor bound to peptide:MHC class II with bound CD4 (Fig. 4.28). This structure demonstrates that the CD4 molecule and the T-cell receptor can bind simultaneously to the same peptide:MHC class II complex. CD4 enhances sensitivity to antigen, as the T cell is about 100-fold more sensitive to the antigen when CD4 is present. The enhancement process results from the ability of the intracellular portion of CD4 to bind to a cytoplasmic tyrosine kinase called Lck. As we will discuss in detail Chapter 7, bringing Lck into proximity with the T-cell receptor complex helps activate the signaling cascade induced by antigen recognition.
The structure of CD8 is quite different. It is a disulfide-linked dimer of two different chains, called αand β, each containing a single Ig-like domain linked to the membrane by a segment of extended polypeptide (see Fig. 4.26). This segment