CHARACTERIZING THE ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I CYTOPLASMIC DOMAIN IN INTRACELLULAR PDZ SIGNALING

Abstract

Members of the major histocompatibility complex class I (MHCI) are known for their roles in the immune system, and also negatively regulate synaptic transmission and plasticity mediated by N-methyl-D-aspartate receptors (NMDARs) in the nervous system. Proper control of NMDAR function is essential for normal synaptic plasticity and learning and memory, and NMDAR dysfunction is a core element of neurological disorders including schizophrenia. Therefore, it is of fundamental importance to understand how NMDARs are regulated, and how they may become dysregulated in disease states. In this dissertation, I also show that MHCI contributes to developmental and aging-related loss of nerve-muscle synapses. While much is known about the mediators of MHCI’s immune functions, the molecular mechanisms by which MHCI regulates NMDARs remains unknown. This dissertation is mainly focused on understanding the molecular mechanisms by which MHCI regulates excitatory synaptic transmission, using a combination of bioinformatic, biochemical, and electrophysiological approaches. Most MHCI proteins are single-pass transmembrane proteins with a short (~40 amino acid) cytoplasmic domain (CD). All known immune signaling by MHCI involves immunoreceptors or cofactors binding to the extracellular domain of MHCI, while the cytoplasmic domain of MHCI is largely dispensable. However, we identified cryptic protein-protein interaction motifs within the MHCI CD using bioinformatics approaches, hinting at as-yet unknown functions. Indeed, electrophysiological studies demonstrated that the cytoplasmic domain of MHCI mediates its effects on synaptic transmission. To begin to understand signaling via MHCI’s cytoplasmic domain, three novel binding partners for the MHCI CD were identified in neurons, using biochemical approaches. I found that specific residues in the MHCI CD are necessary for these protein interactions, and phosphorylation of these same residues can disrupt binding, suggesting a rapid mechanism for MHCI functional control. Overall, this dissertation identifies a new and important role for the MHCI CD in neurons. Since MHCI is expressed on nearly all nucleated cells in the body, it is possible that the cytoplasmic signaling identified here contributes to pleiotropic functions of MHCI in other cell types.