8536d_cho7 161-184 8/16/02 12: 09 PM Page 166 mac100 mac 100: 1?/8_tm: 8536d: Goldsby et al./Immunology Se 166 PART I1 Generation of B-Cell and T-Cell Response between strains that differ in only a few genes within the Class I Molecules Have a Glycoprotein Heavy MHC. Furthermore, the generation of new H-2 haplotypes Chain and a Small Protein Light Chain under the experimental conditions of congenic strain devel opment provides an excellent illustration of the means by Class I MHC molecules contain a 45-kilodalton(kDa)a which the MHC continues to maintain heterogeneity even in chain associated noncovalently with a 12-kDa B2-microglob populations with limited diversity. brane glycoprotein encoded by polymorphic genes within the A,B, and C regions of the human HLA complex and within the K and D/L regions of the mouse H-2 complex(see Figure MHC Molecules and Genes 7-1). B2-Microglobulin is a protein encoded by a highly con- served gene located on a different chromosome. Association Class I and class II MHC molecules are membrane-bound of the a chain with B2-microglobulin is required for expres- glycoproteins that are closely related in both structure and sion of class I molecules on cell membranes. The a chain is function. Both class I and class II MHC molecules have been anchored in the plasma membrane by its hydrophobic trans isolated and purified and the three-dimensional structures membrane segment and hydrophilic cytoplasmic tail. of their extracellular domains have been determined by x Structural analyses have revealed that the a chain of class I ay crystallography. Both types of membrane glycoproteins MHC molecules is organized into three external domains function as highly specialized antigen-presenting molecules (al, a2, and a3), each containing approximately 90 amino that form unusually stable complexes with antigenic pep- acids; a transmembrane domain of about 25 hydrophobic tides, displaying them on the cell surface for recognition by amino acids followed by a short stretch of charged(hy T cells. In contrast, class III MHC molecules are a group of drophilic)amino acids; and a cytoplasmic anchor segment of unrelated proteins that do not share structural similarity 30 amino acids. The B2-microglobulin is similar in size and and common function with class I and II molecules. The organization to the a3 domain; it does not contain a trans- class lll molecules will be examined in more detail in later membrane region and is noncovalently bound to the class I chapters glycoprotein Sequence data reveal homology between the a3 Class i molecule Class ll molecule membrane. distal Membrane-proximal a3 β2 microglobulin a2 β2 domains (g-fold structure) Transmembrane segment Cytoplasmic tail FIGURE7-5Schematic diagrams of a class I and a class ll MHc membrane-proximal domains possess the basic immunoglobulin- molecule showing the external domains, transmembrane segment, fold structure; thus, class l and class ll MHC molecules are classified and cytoplasmic tail. The peptide-binding cleft is formed by the mem. as members of the immunoglobulin superfamily. brane- distal domains in both dass i and class ll molecules. Thebetween strains that differ in only a few genes within the MHC. Furthermore, the generation of new H-2 haplotypes under the experimental conditions of congenic strain devel￾opment provides an excellent illustration of the means by which the MHC continues to maintain heterogeneity even in populations with limited diversity. MHC Molecules and Genes Class I and class II MHC molecules are membrane-bound glycoproteins that are closely related in both structure and function. Both class I and class II MHC molecules have been isolated and purified and the three-dimensional structures of their extracellular domains have been determined by x￾ray crystallography. Both types of membrane glycoproteins function as highly specialized antigen-presenting molecules that form unusually stable complexes with antigenic pep￾tides, displaying them on the cell surface for recognition by T cells. In contrast, class III MHC molecules are a group of unrelated proteins that do not share structural similarity and common function with class I and II molecules. The class III molecules will be examined in more detail in later chapters. Class I Molecules Have a Glycoprotein Heavy Chain and a Small Protein Light Chain Class I MHC molecules contain a 45-kilodalton (kDa) chain associated noncovalently with a 12-kDa 2-microglob￾ulin molecule (see Figure 7-5). The chain is a transmem￾brane glycoprotein encoded by polymorphic genes within the A, B, and C regions of the human HLA complex and within the K and D/L regions of the mouse H-2 complex (see Figure 7-1). 2-Microglobulin is a protein encoded by a highly con￾served gene located on a different chromosome. Association of the chain with 2-microglobulin is required for expres￾sion of class I molecules on cell membranes. The chain is anchored in the plasma membrane by its hydrophobic trans￾membrane segment and hydrophilic cytoplasmic tail. Structural analyses have revealed that the chain of class I MHC molecules is organized into three external domains (1, 2, and 3), each containing approximately 90 amino acids; a transmembrane domain of about 25 hydrophobic amino acids followed by a short stretch of charged (hy￾drophilic) amino acids; and a cytoplasmic anchor segment of 30 amino acids. The 2-microglobulin is similar in size and organization to the 3 domain; it does not contain a trans￾membrane region and is noncovalently bound to the class I glycoprotein. Sequence data reveal homology between the 3 166 PART II Generation of B-Cell and T-Cell Responses α1 α2 β1 β2-microglobulin β2 Transmembrane segment Cytoplasmic tail α2 α1 α3 S Class I molecule Class II molecule S S S S S S S S S S S Peptide-binding cleft Membrane-distal domains Membrane-proximal domains (Ig-fold structure) FIGURE 7-5 Schematic diagrams of a class I and a class II MHC molecule showing the external domains, transmembrane segment, and cytoplasmic tail. The peptide-binding cleft is formed by the mem￾brane-distal domains in both class I and class II molecules. The membrane-proximal domains possess the basic immunoglobulin￾fold structure; thus, class I and class II MHC molecules are classified as members of the immunoglobulin superfamily. 8536d_ch07_161-184 8/16/02 12:09 PM Page 166 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: