Tapasin and other chaperones: models of the MHC class I loading complex

Abstract

MHC (major histocompatibility complex) class I molecules bind intracellular virus-derived peptides in the endoplasmic reticulum (ER) and present them at the cell surface to cytotoxic T lymphocytes. Peptide-free class I molecules at the cell surface, however, could lead to aberrant T cell killing. Therefore, cells ensure that class I molecules bind high-affinity ligand peptides in the ER, and restrict the export of empty class I molecules to the Golgi apparatus. For both of these safeguard mechanisms, the MHC class I loading complex (which consists of the peptide transporter TAP, the chaperones tapasin and calreticulin, and the protein disulfide isomerase ERp57) plays a central role. This article reviews the actions of accessory proteins in the biogenesis of class I molecules, specifically the functions of the loading complex in high-affinity peptide binding and localization of class I molecules, and the known connections between these two regulatory mechanisms. It introduces new models for the mode of action of tapasin, the role of the class I loading complex in peptide editing, and the intracellular localization of class I molecules.

Immunogenic death of colon cancer cells treated with oxaliplatin

“…Reduced calreticulin expression also has a negative impact on neuroblastoma (Hsu et al, 2005), cervical carcinoma (Mehta et al, 2008), as well as on follicular thyroid carcinoma (Netea-Maier et al, 2008). Hence, it will be important to investigate whether CRT affects the immunogenicity of such tumors beyond its role in contributing to optimal peptide loading into major histocompatibility complex class I antigen (Wright et al, 2004;Zhang and Williams, 2006). Second, failure of the immune system to perceive immunogenic signals would have a negative influence on the efficacy of chemotherapy.…”

Tapasin edits peptides on MHC class I molecules by accelerating peptide exchange

“…In molecular dynamics simulations, the a 2 -1 helix is highly flexible in the absence of peptide or during its dissociation [39], and its flexibility differs greatly between tapasin-dependent and -independent class I molecules [37,40]. Since the a 2 -1 helix forms three hydrogen bonds with the C-terminal region of the peptide, from Thr-143, Lys-146, and Trp-147, its movement away from the peptide, perhaps mediated by tapasin, would significantly decrease the overall peptide binding affinity of a class I molecule [1,41] but also open up the groove to allow peptides to bind and dissociate more rapidly [40]. Such an opened structure would have the kinetic properties of the transition state C z that was postulated above.…”

“…The peptides (usually 8-10 aa in length) are generated in the cytosol and transported into the endoplasmic reticulum (ER), where they bind to the newly synthesized class I heterodimer, which consists of the heavy chain (HC) and beta-2 microglobulin (b 2 m). For most class I allotypes, optimal peptide loading (prior to exit toward the cell surface) requires an interaction with the peptide loading complex (PLC), which consists of the peptide transporter TAP, the lectin chaperone calreticulin, the protein disulfide isomerases ERp57 and possibly PDI, and the class I-specific peptide loading factor, tapasin [1,2]. In the PLC, class I binds directly to tapasin [3].…”

Intracellular peptide transporters in human – compartmentalization of the “peptidome”

“…Within a macromolecular peptide-loading complex (∼1 MDa) composed of various auxiliary factors such as the ER resident chaperones tapasin, calreticulin, and the oxidoreductase ERp57, peptides are efficiently transferred from TAP to MHC class I molecules [18,45,94]. Tapasin, a type I membrane glycoprotein consisting of two immunoglobulin folds and of an N-terminal domain, bears several important functions in the peptide-loading complex.…”