The biosynthetic pathway for MHC class II molecules begins with their translocation into the endoplasmic reticulum. Here, it is important to prevent them from prematurely binding to peptides transported into the endoplasmic reticulum lumen or to the cell’s own newly synthesized polypeptides. The endoplasmic reticulum is full of unfolded and partly folded polypeptide chains, and so a general mechanism is needed to prevent these from binding in the open-ended peptide-binding groove of the MHC class II molecule. Premature peptide binding is prevented by the assembly of newly synthesized MHC class II molecules with a membrane protein known as the MHC class II-associated invariant chain (Ii, CD74). Ii is a type II membrane glycoprotein; its amino terminus resides in the cytosol and its transmembrane region spans the membrane of the endoplasmic reticulum (Fig. 6.11). The remainder of Ii and its carboxy terminus reside within the endoplasmic reticulum. Ii has a unique cylindrical domain that mediates formation of stable Ii trimers. Near this domain, Ii contains a peptide sequence, the class II-associated invariant chain peptide (CLIP), with which each Ii subunit of the trimer binds noncovalently to an MHC class II α:β heterodimer. Each Ii subunit binds to an MHC class II molecule with CLIP lying within the peptide-binding groove, thus blocking the groove and preventing the binding of either peptides or partly folded proteins. The binding site of an MHC class II molecule is open relative to the binding site of an MHC class I molecule.
Invariant chain (Ii) binds in the groove of MHC class II molecule Ii is cleaved initially to leave a fragment bound to the class II molecule and to the membrane Further cleavage leaves a short peptide fragment, CLIP, bound to the class II molecule Ii LIP10 cytosol ER C terminus trimerization domain transmembrane domainN terminus CLIP CLIP
Fig. 6.11 The invariant chain is cleaved to leave a peptide fragment, CLIP, bound to the MHC class II molecule.
A model of the trimeric invariant chain bound to MHC class II α:β heterodimers is shown on the left. The CLIP portion is shown in purple, the rest of the invariant chain is shown in green, and the MHC class II molecules are shown in yellow (model, and leftmost of the three panels). In the endoplasmic reticulum, the invariant chain (Ii) binds to MHC class II molecules with the CLIP section of its polypeptide chain lying along the peptide-binding groove. After transport into an acidified vesicle, Ii is cleaved, initially just at one side of the MHC class II molecule (center panel), first by non-cysteine proteases to give a remaining portion of Ii known as the leupeptin-induced peptide LIP22 (not shown), and then by cysteine protease to the LIP10 fragment shown. LIP10 retains the transmembrane and cytoplasmic segments that contain the signals that target Ii:MHC class II complexes tothe endosomal pathway. Subsequent cleavage (right panel) of LIP10 leaves only a short peptide still bound by the class II molecule; this peptide is the CLIP fragment. Model structure courtesy of P. Cresswell.