Chapter 26 - The Transporter Associated with Antigen Processing (TAP): A Peptide Transport and Loading Complex Essential for Cellular Immune Response

Abstract

MHC class I molecules are composed of a polymorphic heavy chain (α-chain), which is encoded within the MHC locus, and an invariant nonMHC encoded subunit. The assembly of the different subunits proceeds in the ER by a folding process that is synchronized in time and space by various chaperones. After cotranslational translocation, the α-chain of the MHC class I molecule associates with the chaperone protein, calnexin, and forms a dimer with β2-microglobulin. β2-Microglobulin interacts extensively with domains of the α-chain and, consequently, the correct folding of the α-chain is dependent on the dimerization with 2-microglobulin. Calnexin is then replaced by another chaperone, calreticulin, and the thiol reductase ERp57 then associates with the complex. For the binding of peptides to the MHC class I heterodimer, a macromolecular loading complex, together with tapasin and an ATP-binding cassette (ABC) heterodimeric protein known as the transporter associated with antigen processing (TAP) (ABCB2/ABCB3), is formed. The transport of the peptides generated in the cytosol into the ER lumen is executed by TAP (ABCB2/ABCB3). Since peptide binding is necessary for stabilization of the MHC complex, a reduced or abolished transport activity of TAP results in reduced cell surface expression of MHC class I molecules. Thus, TAP function is essential for antigen presentation and, consequently, inhibition of TAP function is an effective strategy for pathogens to avoid immune surveillance.