15.13:
Protein Folding Quality Check in the RER
In the ER lumen, an unfolded polypeptide has multiple precursor N-linked glycans attached to it.
These precursor glycans are branched oligosaccharides, each with three terminal glucose residues.
Two of these glucose residues are sequentially removed by the action of glucosidase I and glucosidase II, leaving behind a trimmed N-linked oligosaccharide with a single glucose.
The membrane-bound calnexin and soluble calreticulin are lectin chaperones, which specifically bind such monoglucosylated trimmed glycans.
The lectins then recruit other chaperones to assist in polypeptide folding.
Soon after, glucosidase II trims out the final glucose residue, creating non-glucosylated glycans on the polypeptide.
The UDP-glucose:glycoprotein glucosyltransferase 1, or UGGT1 enzyme, then assesses the protein for its folding accuracy.
If the folding is correct, the protein is allowed to exit the ER. Otherwise, UGGT1 adds a glucose molecule from UDP-glucose back to the glycan attached to the polypeptide.
The reglucosylation recycles the polypeptide for another round of folding by calnexin/calreticulin chaperones until the correct protein structure is achieved.
15.13:
Protein Folding Quality Check in the RER
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm for degradation.
Lectin Chaperone System: The Glycoprotein Binding Proteins
The lectin chaperones — calnexin, and calreticulin are distinguished from other ER chaperones due to their ability to bind N-linked glycans. The N-linked glycans are abundantly present on most polypeptide chains entering the ER lumen, and the lectins utilize this modification for proofreading the accuracy of protein folding. Calnexin and calreticulin, both have very similar functional domains. They primarily bind mono-glucosylated N-linked glycans using their glycan-binding lectin domain, and use the P-domain on their flexible arm to interact with other ER chaperones.
Lectin Binding ER Chaperones: The Accessory Helpers
Three functionally distinct ER chaperones — Erp57, cyclophilin B, and Erp29, assist the calnexin/calreticulin proteins. ERp57 is a protein disulfide isomerase that catalyzes the oxidation and isomerization of disulfide bonds. While cyclophilin B rearranges and corrects the disulfide bonds, ERp29 is a general chaperone that aids peptide folding.
UDP-glucose:glycoprotein Glucosyltransferase 1: The Proofreader
UDP-glucose:glycoprotein glucosyltransferase 1, or UGGT1, a protein folding sensor, binds polypeptide and acts as the single glycoprotein folding quality control checkpoint. It marks incorrectly folded glycoproteins to be retained in the ER by selective reglucosylation. The N-terminal of UGGT acts as the misfold sensor, whereas the C-terminal harbors the reglucosylating glucosyltransferase.
Suggested Reading
- Tannous, Abla, Giorgia Brambilla Pisoni, Daniel N. Hebert, and Maurizio Molinari. "N-linked sugar-regulated protein folding and quality control in the ER." In Seminars in cell & developmental biology, vol. 41, pp. 79-89. Academic Press, 2015.
- Ferris, Sean P., Vamsi K. Kodali, and Randal J. Kaufman. "Glycoprotein folding and quality-control mechanisms in protein-folding diseases." Disease models & mechanisms 7, no. 3 (2014): 331-341.
- Słomińska-Wojewódzka, Monika, and Kirsten Sandvig. "The role of lectin-carbohydrate interactions in the regulation of ER-associated protein degradation." Molecules 20, no. 6 (2015): 9816-9846.