8536d ch07161-184 8/16/02 12: 09 PM Page 168 mac100 mac 100: 1258 tm: 8536d: Goldsby et al. Immunology 5e 168 PART I1 Generation of B-Cell and T-Cell Response Class ll molecules have two nonidentical Glycoprotein Chains Class II MHC molecules contain two different polypeptide hains, a 33-kDa a chain and a 28-kDa B chain, which asso ciate by noncovalent interactions(see Figure 7-5b) Like class I a chains, class II MHC molecules are membrane-bound glycoproteins that contain external domains, a transmem- brane segment, and a cytoplasmic anchor segment. Each chain in a class ii molecule contains two external domains. I and a2 domains in one chain and Bl and B2 domains in the other. The membrane-proximal a2 and B2 domains, like the membrane-proximal a3/B2-microglobulin domains of class I MHC molecules, bear sequence similarity to the im- munoglobulin-fold structure; for this reason, class II MHC (b) molecules also are classified in the immunoglobulin super- family. The membrane-distal portion of a class II molecule is composed of the al and Bl domains and forms the antigen binding cleft for processed antigen X-ray crystallographic analysis reveals the similarity of lass II and class I molecules, strikingly apparent when the molecules are surperimposed( Figure 7-7). The peptide binding cleft of HLA-DRl, like that in class I molecules, is composed of a floor of eight antiparallel B strands and side of antiparallel a helices. However, the class Il molecule lacks the conserved residues that bind to the terminal residues of short peptides and forms instead an open pocket; class I pre sents more of a socket, class ll an open-ended groove. Thas functional consequences of these differences fine structure will be explored beloy An unexpected difference between crystallized class I and class li molecules was observed for human dri in that the FIGURE7-8Antigen-binding cleft of dimeric class ll DR1 molecule in(a) top view and (b) side view. This molecule crystallized as a dimer of the ap heterodimer. The crystallized dimer is shown with one dri molecule in red and the other dri molecule in blue. the bound peptides are yellow. The two peptide- binding clefts in the dimeric molecule face in opposite directions. From H Brown et al 1993. Nature364:33J latter occurred as a dimer of aB heterodimers, a" dimer of dimers"(Figure 7-8). The dimer is oriented so that the two peptide-binding clefts face in opposite directions. While it has not yet been determined whether this dimeric form exists in vivo, the presence of CD4 binding sites on opposite sides of the class Il molecule suggests that it does. These two sites on the a2 and B2 domains are adjacent in the dimer form and a CD4 molecule binding to them may stabilize class ll dimers The Exon/Intron Arrangement of Class I and FIGURE 7.7 The membrane-distal, peptide-binding cleft of a hu. ll Genes Reflects Their Domain Structure man class Il MHC molecule, HLA-DR1 (blue perimposed over Separate exons encode each region of the class I and ll pro the corresponding regions of a human class I MHC molecule, HLA- teins( Figure 7-9). Each of the mouse and human class I A2(red). From/ H. Brown et aL., 1993, Nature 364: 33. J genes has a 5' leader exon encoding a short signal peptideClass II Molecules Have Two Nonidentical Glycoprotein Chains Class II MHC molecules contain two different polypeptide chains, a 33-kDa chain and a 28-kDa  chain, which asso￾ciate by noncovalent interactions (see Figure 7-5b). Like class I chains, class II MHC molecules are membrane-bound glycoproteins that contain external domains, a transmem￾brane segment, and a cytoplasmic anchor segment. Each chain in a class II molecule contains two external domains: 1 and 2 domains in one chain and 1 and 2 domains in the other. The membrane-proximal 2 and 2 domains, like the membrane-proximal 3/2-microglobulin domains of class I MHC molecules, bear sequence similarity to the im￾munoglobulin-fold structure; for this reason, class II MHC molecules also are classified in the immunoglobulin super￾family. The membrane-distal portion of a class II molecule is composed of the 1 and 1 domains and forms the antigen￾binding cleft for processed antigen. X-ray crystallographic analysis reveals the similarity of class II and class I molecules, strikingly apparent when the molecules are surperimposed (Figure 7-7). The peptide￾binding cleft of HLA-DR1, like that in class I molecules, is composed of a floor of eight antiparallel  strands and sides of antiparallel helices. However, the class II molecule lacks the conserved residues that bind to the terminal residues of short peptides and forms instead an open pocket; class I pre￾sents more of a socket, class II an open-ended groove. These functional consequences of these differences in fine structure will be explored below. An unexpected difference between crystallized class I and class II molecules was observed for human DR1 in that the latter occurred as a dimer of  heterodimers, a “dimer of dimers” (Figure 7-8). The dimer is oriented so that the two peptide-binding clefts face in opposite directions. While it has not yet been determined whether this dimeric form exists in vivo, the presence of CD4 binding sites on opposite sides of the class II molecule suggests that it does. These two sites on the 2 and 2 domains are adjacent in the dimer form and a CD4 molecule binding to them may stabilize class II dimers. The Exon/Intron Arrangement of Class I and II Genes Reflects Their Domain Structure Separate exons encode each region of the class I and II pro￾teins (Figure 7-9). Each of the mouse and human class I genes has a 5 leader exon encoding a short signal peptide 168 PART II Generation of B-Cell and T-Cell Responses FIGURE 7-7 The membrane-distal, peptide-binding cleft of a hu￾man class II MHC molecule, HLA-DR1 (blue), superimposed over the corresponding regions of a human class I MHC molecule, HLA￾A2 (red). [From J. H. Brown et al., 1993, Nature 364:33.] (a) (b) FIGURE 7-8 Antigen-binding cleft of dimeric class II DR1 molecule in (a) top view and (b) side view. This molecule crystallized as a dimer of the  heterodimer. The crystallized dimer is shown with one DR1 molecule in red and the other DR1 molecule in blue. The bound peptides are yellow. The two peptide-binding clefts in the dimeric molecule face in opposite directions. [From J. H. Brown et al., 1993, Nature 364:33.] 8536d_ch07_161-184 8/16/02 12:09 PM Page 168 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: