Molecular chaperones in major histocompatibility complex (MHC) class I folding and assembly.
Mancino, Laura
2003
Abstract
Major histocompatibility complex (MHC) class I molecules present antigenic peptides to cytotoxic T lymphocytes. This antigen recognition system is critically important for immunesurveillance against viruses and tumors. MHC class I molecules consist of a transmembrane glycoprotein (heavy chain), a small soluble protein (beta2m), and a short peptide. The assembly of class I molecules in the endoplasmic reticulum is assisted by several accessory proteins that form the MHC class I loading complex. To facilitate the definition of the individual functions played by the various proteins that facilitate MHC class I folding and assembly in the ER, we focused our research on two homologous lectins, calreticulin and calnexin. The approach used was to analyze the effect of calreticulin and calnexin on folding and assembly of MHC class I molecules, using purified proteins <italic> in vitro</italic>. Or studies have indicated that calnexin and calreticulin associate with unfolded MHC class I heavy chains, preventing their aggregation, and maintaining them in a folding-competent state. However, in the absence of other ER factors, calreticulin and calnexin, by themselves, did not enhance peptide binding by class I molecules. Importantly, we provide evidence that the functional interactions between calreticulin and HLA-A2 molecules are mediated by direct recognition of misfolded polypeptide regions of class I heavy chains. Next, we have shown that calreticulin undergoes profound structural changes in response to heat shock and other types of cellular stress. These structural changes allow for oligomerization of the chaperone, and simultaneously for enhanced chaperone activity towards MHC class I molecules. However, oligomerization <italic> per se</italic> is not essential for enhancement in calreticulin s chaperone activity. Finally, we compared the chaperone activities of structurally related chaperones calreticulin and calnexin, and the structurally unrelated immunoglobulin binding protein (BiP). We showed that calreticulin and calnexin share many similarities in their modes of function. Both proteins oligomerize in response to heat shock, including the formation of disulfide-linked dimers as well as high molecular weight species. Heat-induced structural changes contribute to enhanced chaperone activities of both proteins. By contrast to calreticulin and calnexin, BiP is able to efficiently suppress the aggregation of class I molecules without the requirement for heat-induced structural changes. Our studies suggest that distinct conformations of the lectin chaperones calreticulin and calnexin may function in oligosaccharide and polypeptide binding, allowing for two distinct modes of misfolded protein recognition.Subjects
Assembly Calnexin Complex Folding Histocompatibility Major Mhc Class I Molecular Chaperones
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