Intracellular Signal Transduction by MHCI: Requirements and Regulation

Abstract

Proteins of the major histocompatibility complex class I (MHCI) are well known for their involvement in the adaptive immune response. More recently, MHCI was identified as an endogenous regulator of hippocampal N-methyl-D-aspartate receptors (NMDARs). A recent study from the Boulanger Lab investigated conserved PDZ ligands within the MHCI cytoplasmic domain. Furthermore, preliminary results from the Boulanger Lab suggest that MHCI regulates NMDARs via PDZ interactions with intermediary synaptic proteins. My thesis expands upon these findings and identifies phosphorylation of the MHCI cytoplasmic domain as a potential mechanism for regulating binding to PDZ domain-containing proteins. Precise NMDAR function is critical for development and synaptic plasticity, with hypoactivity or hyperactivity of NMDARs associated with excitotoxicity/injury and neurological disorders. Thus, it would be important for MHCI to have a mechanism to rapidly regulate the interactions with its intermediary proteins in order to maintain tight control over NMDARs. In this thesis, I investigate the role of phosphorylation of key cytoplasmic residues, specifically the classical mouse MHCI gene H2-K’s tyrosine 321 (Y321), which is critical for these protein-protein interactions. MHCI’s interactions with two novel PDZ binding partners, PSD-95 and spinophilin, are studied, at the amino acid level, to better characterize the requirements for binding and to explore phosphorylation regulatory mechanisms. A better understanding of how to control MHCI’s effects on NMDARs could provide insight into how to treat NMDAR dysfunction, which may play central roles in disorders including schizophrenia, traumatic brain injury, and stroke.