On the structure-function of MHC class II molecules and how single amino acid polymorphisms could alter intracellular trafficking.

Classical HLA class II molecules are highly polymorphic heterodimeric transmembrane proteins encoded by a polygenic cluster on chromosome 6. Polymorphic residues in the membrane-distal domains ensure that a large collection of microbial peptides can be bound in the human population. Still, the HLA-DR, -DP and -DQ isotypes show a high degree of conservation in their overall tertiary and quaternary structures, in line with their common function in T cell receptor activation. Interestingly, the primary structure of the intracellular domains are highly divergent between isotypes and they also show allotypic variations. The functional impact of these differences remains to be fully appreciated. Here, we address the role of the MHC class II cytoplasmic tails in intracellular trafficking. First, the emphasis will be on the interplay between the cytoplasmic domains of classical human MHC class II molecules and those of the invariant chain chaperone (CD74) isoforms. Then, we will examine the importance of the highly conserved β-chain cytoplasmic lysine residue in the ubiquitin-driven trafficking of MHC class II molecules. These considerations should help understand the potential functional impact of sequence variations that may arise in the cytoplasmic tails and transmembrane domains of MHC class II molecules.