Abstract
BackgroundMajor histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity. Most MHCI are transmembrane proteins. The extracellular domain of MHCI interacts with immunoreceptors, peptides, and co-receptors to mediate immune signaling. While the cytoplasmic domain also plays important roles in endocytic trafficking, cross-presentation of extracellularly derived antigens, and CTL priming, the molecular mediators of cytoplasmic signaling by MHCI remain largely unknown.ResultsHere we show that the cytoplasmic domain of MHCI contains putative protein-protein interaction domains known as PDZ (PSD95/disc large/zonula occludens-1) ligands. PDZ ligands are motifs that bind to PDZ domains to organize and mediate signaling at cell-cell contacts. PDZ ligands are short, degenerate motifs, and are therefore difficult to identify via sequence homology alone, but several lines of evidence suggest that putative PDZ ligand motifs in MHCI are under positive selective pressure. Putative PDZ ligands are found in all of the 99 MHCI proteins examined from diverse species, and are enriched in the cytoplasmic domain, where PDZ interactions occur. Both the position of the PDZ ligand and the class of ligand motif are conserved across species, as well as among genes within a species. Non-synonymous substitutions, when they occur, frequently preserve the motif. Of the many specific possible PDZ ligand motifs, a handful are strikingly and selectively overrepresented in MHCI’s cytoplasmic domain, but not elsewhere in the same proteins. Putative PDZ ligands in MHCI encompass conserved serine and tyrosine residues that are targets of phosphorylation, a post-translational modification that can regulate PDZ interactions. Finally, proof-of-principle in vitro interaction assays demonstrate that the cytoplasmic domains of particular MHCI proteins can bind directly and specifically to PDZ1 and PDZ4&5 of MAGI-1, and identify a conserved PDZ ligand motif in the classical MHCI H2-K that is required for this interaction.ConclusionsThese results identify cryptic protein interaction motifs in the cytoplasmic domain of MHCI. In so doing, they suggest that the cytoplasmic domain of MHCI could participate in previously unsuspected PDZ mediated protein-protein interactions at neuronal as well as immunological synapses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0154-z) contains supplementary material, which is available to authorized users.
Highlights
Major histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity
Multiple bioinformatic analyses suggest that PSD-95/discs large/zonula occludens-1 (PDZ) ligand motifs in the cytoplasmic domain of MHCI are under positive selective pressure, and biochemical assays demonstrate that the cytoplasmic domain of MHCI can bind directly and to PDZ domains in vitro
PDZ ligand motifs are found in the cytoplasmic domain of mouse and human MHCI proteins Previous studies identified conserved tyrosine and serine residues in the cytoplasmic domain of MHCI immune proteins, some of which can be phosphorylated in vivo and in vitro [14, 15, 20, 26,27,28,29,30,31,32,33,34], but the functional importance of these conserved residues has remained largely unknown
Summary
Major histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity. While the cytoplasmic domain plays important roles in endocytic trafficking, cross-presentation of extracellularly derived antigens, and CTL priming, the molecular mediators of cytoplasmic signaling by MHCI remain largely unknown. The major histocompatibility complex class I (MHCI) is a multi-gene family known for its roles in the immune response. Non-classical MHCI proteins (HLA-E, −F, and –G in humans; members of the H2T, −Q, and -M gene clusters in mice) present more specialized peptide or lipid repertoires, or are physically incapable of presenting antigen, and their functions are relatively poorly understood. Despite the important roles of MHCI in determining neuronal structure and function, the protein interactions that mediate MHCI’s non-immune functions in neurons have not been identified
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