Getting in and out from calnexin/calreticulin cycles

Abstract

The N-glycan-dependent quality control mechanism of glycoprotein folding was proposed initially by Helenius and coworkers several years ago; with a few minor modifications, it is still valid today (Fig. 1) (1–3).2 Glycan processing starts immediately after its transfer from a dolichol-P-P derivative to Asn residues in nascent polypeptide chains entering the lumen of the ER.3 Removal of the outermost and following glucoses by the successive action of GI and GII exposes the Glc1Man9GlcNAc2 epitope (Fig. 2). This structure is then recognized by two ER resident lectins (CNX and CRT) that specifically bind monoglucosylated polymannose glycans. This is followed by removal of the innermost glucose by GII, thus liberating the glycoprotein from the lectin anchor. The proteinlinked glycan is then reglucosylated by the soluble ER enzyme GTonly if the protein moiety displays non-native three-dimensional structures, as this enzyme behaves as a conformational sensor. Cycles of CNX/CRT-glycoprotein binding and liberation, catalyzed by the opposing activities of GT and GII, are terminated once glycoproteins attain their native structures. Glucose-free glycoproteins then continue their transit through the secretory pathway. Alternatively, permanently misfolded glycoproteins may be then transported to the cytosol for proteasomal degradation. Lectin-glycoprotein association not only thwarts Golgi exit of folding intermediates and irreparably misfolded glycoproteins but also enhances folding efficiency by preventing aggregation and promoting proper disulfide bonding. The latter is catalyzed by an oxidoreductase of the proteindisulfide isomerase family (ERp57) that acts exclusively on glycoproteins, as it is loosely associated with CNX/CRT