Major histocompatibility complex (MHC) molecules are only found in jawed vertebrates and not in more primitive species. MHC class II type structures likely represent the ancestral structure of MHC molecules. Efficient MHC class II transport to endosomal compartments depends on association with a specialized chaperone, the MHC class II invariant chain (aliases Ii or CD74). The present study identifies conserved motifs in the CLIP region of CD74 molecules, used for binding in the MHC class II binding groove, throughout jawed vertebrates. Peculiarly, in CD74a molecules of Ostariophysi, a fish clade including for example Mexican tetra and zebrafish, the CLIP region has duplicated. In mammals, in endosomal compartments, the peptide-free form of classical MHC class II is stabilized by binding to nonclassical MHC class II “DM,” a process that participates in “peptide editing” (selection for high affinity peptides). Hitherto, DM-lineage genes had only been reported from the level of amphibians, but the present study reveals the existence of DMA and DMB genes in lungfish. This is the first study which details how classical and DM lineage molecules have distinguishing glycine-rich motifs in their transmembrane regions. In addition, based on extant MHC class II structures and functions, the present study proposes a model for early MHC evolution, in which, in an ancestral jawed vertebrate, the ancestral MHC molecule derived from a heavy-chain-only antibody type molecule that cycled between the cell surface and endosomal compartments.
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