The quality control system of the endoplasmic reticulum (ER) ensures that only properly folded and correctly assembled proteins are transported from the ER to the Golgi complex and beyond. Calnexin and calreticulin function within the ER quality control system as endogenous lectin-like chaperones for certain proteins containing partially trimmed, monoglucosylated N-linked glycan chains. Although significant evidence exists that calnexin and calreticulin participate in the biosynthesis and assembly of a wide variety of proteins, how these chaperones accomplish their quality control functions at the molecular level is largely unknown. The focus of this proposal is to evaluate the molecular mechanisms that regulate the interaction of T cell antigen receptor (TCR) and major histocompatibility complex (MHC) class I proteins with glycan-specific quality control components in the ER and to determine the role of lectin-like and auxiliary molecular chaperones in the assembly and expression of TCR and MHC class I protein complexes. Therefore, the following aims have been developed:
Aim 1 - To determine the molecular mechanisms that regulate interaction of TCR proteins with glycan-specific quality control components in the ER and facilitate their assembly into multisubunits TCR complexes;
Aim 2 - To identify structural domains on TCR proteins important for their interaction with glycan-specific quality control components in the ER;
Aim 3 - To investigate the capacity and function of glycan processing pathways and calnexin, calreticulin chaperones in the developmental regulation of abTCR assembly in immature CD4+CD8+ thymocytes;
and Aim 4 - To determine the molecular mechanisms that regulate interaction of MHC class I proteins with calnexin, calreticulin chaperones and sustain MHC class I expression under conditions of limited quality control. Evaluating the interaction of TCR and MHC class I protein subunits with lectin-like chaperones is important for understanding the molecular mechanisms that regulate their assembly and expression during lymphocyte development and activation, and is also important for increasing our knowledge about the cellular mechanisms that regulate protein folding and assembly into the ER. These studies are highly significant to human health as both TCR and MHC class I proteins play major roles in the development and function of the immune systems and molecular chaperones have been implicated in multiple human diseases involving defective protein folding.
