The calnexin cycle sub-group is a mixture of structural and molecular biologists looking at different aspects of the calnexin/calreticulin cycle, a subset of endoplasmic reticulum quality control (ERQC). This is a process by which the folding of glycoproteins is ordered and assessed by a series of lectins (glycan binding proteins). During or immediately following translation a large glycan can be added to certain asparagine residues in a process termed N-linked glycosylation. This glycan consists of two N-acetyl-glucosamines, nine mannoses and three terminal glucose residues. The three glucoses are trimmed down to just one by two enzymes termed α-glucosidase I & II. This monoglucosylated glycan is the substrate for calnexin and calreticulin, two proteins which complex with other chaperones such as ERp57 to aid in the folding of the monoglucosylated protein. α -Glucosidase II eventually removes this final glucose residue permitting release from calnexin. If the protein is correctly folded it proceeds to the Golgi for further processing, but if it is incorrectly folded then it can be re-glucosylated by an enzyme called UDP-glucose glycosyltransferase (UGGT 1), allowing it to re-bind calnexin/calreticulin and have another chance at folding correctly. Failure to fold correctly after a certain period leads to degradation of the glycoprotein by ER associated degradataion (ERAD).
Crystal structure of mouse α-glucosidase II in cartoon representation
Eukaryotes have evolved in such a way that proteins normally destined for secretion are retained inside the cell if they are not properly folded. At the heart of this eukaryotic folding quality control system is the UDP-Glucose Glycoprotein Glucosyl Transferase aka UGGT, the single checkpoint enzyme in charge of flagging misfolded glycoproteins for retention.
Several mysteries surround UGGT. Starting from a gaze at its sequence, more than 1200 residues worth of completely unannotated sequence at the N terminus, make it nearly impossible to glean structural and functional understanding from bioinformatics alone.
We know that UGGT targets misfolded glycopeptides to chaperones inside the cell, by sticking a glucose moiety onto them, thus preventing them from prematurely entering their mature protein life.
But quite how this one protein can recognise misfolding of hundreds of different glycoproteins, and only glucosylate the ones that are not properly folded, is difficult to imagine. Nor is it clear if UGGT is only a checkpoint enzyme, or can instead also work with other cell chaperones to improve the folding of its unfortunate substrate glycoproteins.
And what if UGGT and its strict quality control were to do more harm than good to individuals carrying genetic mutations that only partially impair function? In some circumstances we can imagine it may be better for a partially active, slightly misfolded glycoprotein to reach its tissue destination, rather than remain trapped inside the cell by UGGT glucosylation.
We have started working towards the understanding of UGGT structure and function, and hunting for UGGT inihibitors of therapeutic potential. Watch this space!