Precursor N-linked oligosaccharides as codes for glycoprotein folding status

The majority of eukaryotes share a common N-linked oligosaccharide precursor, Glc₃Man₉GlcNAc₂, which is transferred to proteins during glycoprotein biosynthesis. This precursor is then sequentially processed in the endoplasmic reticulum (ER), creating a series of oligosaccharide structures that are recognized as codes by specific lectins and that inform of the folding status of the glycoprotein. For example, the chaperones/ lectins calnexin and calreticulin bind to monoglucosylated oligosaccharides after the excision of the two terminal glucose residues by glucosidases I and II. The last glucose and sometimes one or even two mannose residues are excised, and the resulting structures Man_7-9GlcNAc₂ are recognized by the lectins ERGIC53, VIP36 and others that are involved in transport of glycoproteins to the Golgi. These lectins associate with properly folded glycoproteins that can exit the ER. In contrast, N-linked oligosaccharides on misfolded glycoproteins are more extensively trimmed to Man_5-6GlcNAc₂. A high local concentration of ER mannosidase I in an ER-derived quality control compartment is mainly responsible for this trimming, with the possible participation of other mannosidases. Man_5-6GlcNAc₂ oligosaccharides are then recognized by the lectins OS9 and XTP3-B that target the misfolded glycoprotein for ER-associated degradation.