MHC class I molecules generally bind and present intracellularly derived peptide while class II molecules bind and present extracellularly derived peptide to T cells.
Class I molecules bind intracellular peptides derived from the cytosol within the Endoplasmic Reticulum (ER), presenting them at the cell surface to CD8+ cytotoxic T cells. The binding of peptide is a crucial part of the folding of the molecule. A number of proteins are involved in coordinating the folding of the MHC class I molecule and the binding of the peptide. The assembly begins with the interaction of the heavy chain containing the α1, 2 and 3 extracellular domains with a chaperone molecule Calnexin. Calnexin retains the molecule in a partly folded state in the ER where it assembles with the β2 microglobulin. The partly folded α chain – β2 microglobulin heterodimer then dissociates from Calnexin and binds to the Calnexin homologue Calreticulin. A Peptide Loading Complex (PLC) then recruits the partly folded α chain : β2 microglobulin : Calreticulin MHC class I molecule by the protein Tapasin forming a bridge between the Transporters associated with Antigen Processing (TAP) and the MHC class I molecule. The endoplasmic reticulum oxido-reductases ERp57 is also involved. The MHC class I molecule is only released from the ER until by the binding of peptide. The PLC is involved in peptide editing, with low affinity peptides being replaced with higher affinity ones. Binding high affinity peptide causes the MHC class I molecule to completes its folding. The leads to the PLC disassembling and the MHC class I : peptide complex leaving the ER and being transported to the cell surface.
MHC class I molecules generally bind peptides of length 8 – 10 amino acids which are transported into the ER by TAP. These peptides are generated by the protease complex Proteasome.
The MHC class II molecules bind extracellularly derived peptides which are then presented to CD4+ T helper cells. The binding takes places in the endocytic pathway at a site that is known as the MHC class II containing Compartment (MIIC). The extracellular antigen are taken up into intracellular vesicles in the cell, typically macrophages and dendritic cells and the pH of the endosomes progressively decreases, leading to activation of proteases. This causes the cleavage of the antigen into peptides which can then bind to MHC class II for presentation at the cell surface.
MHC class II molecules are prevented from binding peptide in the ER by a protein known as the Invariant chain (Ii). The Invariant chain is a trimer and each of its subunits binding non-covalently with an MHC class II molecule. The Invariant chain polypeptide blocks the peptide binding groove by lying in it. The chaperon molecule Calnexin, is involved. The fully folded MHC class II molecule – Ii complex is then released from Calnexin and moves either directly into the MIIC or is cycled to the cell surface where it is then internalised into MIIC. Once in the MIIC, Invariant chain is degraded by endosomal proteases, including Cathepsin S and L, leaving a fragment of peptide known as the Class II associated Invariant chain Peptide (CLIP). CLIP is then exchanged for relevant exogenous peptide by HLA-DM, prior to transport of the stable MHC class II – peptide complex to the cell surface.
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