Practice question

Initial processing of N-glycan precursor after transfer to polypeptide is choreographed to interface with lectin chaperone system. After en bloc transfer of Glc3Man9GlcNAc2, ER alpha-glucosidase I removes terminal α1-2 glucose producing diglucosylated species. ER glucosidase II, heterodimer of catalytic α subunit and mannose-6-phosphate receptor homology β subunit that retains enzyme in ER and senses glycan, removes second α1-3 glucose generating monoglucosylated Glc1Man9GlcNAc2 which is specific ligand for lectin chaperones calnexin and calreticulin. Binding to these lectins retains nascent glycoprotein, prevents aggregation, positions it for disulfide formation via associated oxidoreductase ERp57 bound to P-domain arm. Subsequent removal of last glucose by same glucosidase II terminates interaction, allowing properly folded protein to exit to ERGIC via cargo receptor ERGIC-53 and VIPL lectins. If still non-native, folding sensor UGGT adds glucose back. Removal of three glucoses therefore acts as timer governing entry into and exit from calnexin cycle, ensuring proteins undergo at least one chaperone-assisted attempt before forward transport, enhancing folding fidelity and preventing premature secretion of immature glycoproteins that could malfunction extracellularly and trigger immune responses.