Abstract
N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family.
Highlights
Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) with the aid of various molecular chaperones and oxidoreductases, which catalyze oxidation and reduction reactions on their cysteine residues
The thioredoxin-like domain of PDIR does not contain an active catalytic motif, which suggests that a ternary complex CRT-PDIR-ERp72 may function in glycoprotein folding and disulfide bond formation, with PDIR participating in substrate recognition [56]
After α1,2 mannose trimming, natively folded glycoprotein molecules are further processed and targeted to their final destination, whereas misfolded glycoproteins are retrieved to the ER for ER-associated degradation (ERAD) or are recognized by quality control systems that operate in the Golgi complex and are delivered to lysosomes for degradation [101]
Summary
Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) with the aid of various molecular chaperones and oxidoreductases, which catalyze oxidation and reduction reactions on their cysteine residues. Some of the selenoproteins function as oxidoreductases, containing thioredoxin-like domains with one or more selenocysteines instead of cysteine in a catalytic Cys-X-X-Sec or similar motif [12,13,14] In addition to their catalytic activity in disulfide bonding, many of the oxidoreductases were shown to recognize hydrophobic pockets in their substrate proteins, and they are folding sensors. They participate in the recognition of misfolded glycoprotein domains during sugar chain trimming and creation of what was termed the glycan code for targeting to ER-associated degradation (ERAD) [15]. Several oxidoreductases have been found in recent years to associate functionally with the glycan recognition and processing machineries in the ER, which is the focus of this review
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