Figure 1 Genetic organization of the H2 class II region. Genes of known function are represented by filled rectangles.

Figure 2 Gene structure of H2 class II l-A chains. Because of their chromosomal position, p and a genes are transcribed in opposite direction. Filled boxes represent exons; the exon number is above each. Portions of the mature class II protein which each exon encodes are indicated below the exon. L, leader peptide; a1, a2, pi and fi2 encode the external domains: CP, connecting peptide; TM, transmembrane domain; CY, cytoplasmic domain; UT, untranslated region.

domain, the fifth exon encodes the cytoplasmic domain, and the final exon encodes the 3' untranslated (UT) region. The a chain gene structure is similar, except that the fourth exon encodes the connecting peptide, transmembrane and cytoplasmic domains, as well as part of the 3' UT region.

H2 class II genes exist in a number of allelic forms, many of which have been cloned and sequenced. Sequence information reveals that there is extensive polymorphism at the nucleotide level, with the highest variability clustered in several short stretches of protein sequence in the first external protein domain of the Ap, Hp and Aa genes, while there is little variability between alleles of Ea. Most of the predicted amino acid substitutions encoded by these polymorphisms are nonconservative, and are in parts of the class II molecule predicted to form the binding pocket for antigenic peptides. Such variable amino acids can thus alter interactions with peptide, the T cell antigen receptor, or both.

The use of X-ray crystallography, together with chromatography techniques allowing the isolation and characterization of peptides bound in the class II binding pocket, has led to considerable current understanding of the structural constraints regulating class II-peptide interactions. In contrast to the peptide-binding groove of class I MHC molecules, the class II groove is open at both ends. This allows bound peptides to extend beyond the ends of the groove, and accounts for the greater average length and length variation of class II-binding peptides. However, although class II peptides can vary from 12 to 24 amino acids in length, class II molecules form many bonds with both the peptide main chain and side-chains, increasing binding affinity and potentially leading to similar conformation of peptides bound in the groove, despite differences in length and sequence. It is the side-chain contacts which show greatest variation among class II alleles, leading to allele-specific peptide sequence 'motifs'.

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