Newly synthesized MHC class I αchains that enter the endoplasmic reticulum membranes bind to calnexin, a general-purpose chaperone protein that retains the MHC class I molecule in a partly folded state (Fig. 6.8). Calnexin also associates with partly folded T-cell receptors, immunoglobulins, and MHC class II molecules, and so has a central role in the assembly of many immunological as well as non-immunological proteins. When β2-microglobulin binds to the α chain, the partly folded MHC class I α:β2-microglobulin heterodimer dissociates from calnexin and binds to an assembly of proteins called the MHC class I peptide-loading complex (PLC). One component of ubiquitinated protein normal proteins (>70%) ribosome DRiPs (<30%) TAP tapasin ERp57calreticulin MHC class I ˜:˛2m complex is released from calnexin, binds a complex of chaperone proteins (calreticulin, ERp57) and binds to TAP via tapasin peptide fragments proteasome ERAAP˜2m MHC class I nucleus ER cytosol calnexin Partly folded MHC class I ˜ chains bind to calnexin until ˛2-microglobulin binds Cytosolic proteins and defective ribosomal products (DRiPs) are degraded to peptide fragments by the proteasome. TAP delivers peptides to the ER
Fig. 6.8 MHC class I molecules do not leave the endoplasmic reticulum unless they bind peptides. Newly synthesized MHC class I α chains assemble in the endoplasmic reticulum (ER) with the membrane-bound protein calnexin. When this complex binds β2-microglobulin (β2m), the MHC class I α:β2m dimer dissociates from calnexin, and the partly folded MHC class I molecule then binds to the TAP-associated protein tapasin. Two MHC:tapasin complexes may bind with the TAP dimer at the same time. The chaperone molecules ERp57, which forms a heterodimer with tapasin, and calreticulin also bind to form the MHC class I peptide-loading complex. The MHC class I molecule is retained within the ER until released by the binding of a peptide, which completes the folding of the MHC molecule. Even in the absence
A peptide binds the MHC class I molecule and completes its folding. The MHC class I molecule is released from the TAP complex and exported to the cell membrane of infection, there is a continual flow of peptides from the cytosol into the ER. Defective ribosomal products (DRiPs) and proteins marked for destruction by K48-linked polyubiquitin (yellow triangles) are degraded in the cytoplasm by the proteasome to generate peptides that are transported into the lumen of the endoplasmic reticulum by TAP. Some of these peptides will bind to MHC class I molecules. The aminopeptidase ERAAP trims the peptides at their amino termini, allowing peptides that are too long to bind to MHC class I molecules and thereby increasing the repertoire of potential peptides for presentation. Once a peptide has bound to the MHC molecule, the peptide:MHC complex leaves the endoplasmic reticulum and is transported through the Golgi apparatus and finally to the cell surface.
the PLC—calreticulin—is similar to calnexin and probably also has a general