It′s worth noting that misfolding occurs when cysteine residues are mismatched into disulfides. In addition, the formation of disulfide bonds is a key rate-limiting step in protein folding, and the efficiency of spontaneous disulfide bond formation is far lower than that under enzymatic catalysis. Disulfide bonds, which stabilize protein conformation and participate in the regulation of the protein redox process, are very important for the structure, function, and regulation of protein activities. In all cases, the process of generating a natural protein conformation involves both disulfide bonds formation and isomerization steps. Moreover, redox-active molecules, such as glutathione (GSH), oxidized glutathione (GSSG), thiol compounds, and so on, also exhibit significant effects on the rates of oxidative protein folding and the yield of native proteins. It may be the most complicated protein folding scenario, due to the possibility of protein misfolding being increased with increasing cysteine numbers in a protein, where only one disulfide bond pattern is proper for the correct folding. Oxidative protein folding is a special protein-folding process accompanied by the formation of disulfide bond(s). The theory of molecular chaperones-assisted self-assembly does not necessarily conflict with the thermodynamic hypothesis established by Anfinsen, but rather expands the protein folding theory from a kinetic perspective. Molecular chaperones are a large and diverse group of proteins that share the capability of assisting noncovalent folding and unfolding, the assembly and disassembly of other macromolecular structures, while they would not become a permanent part of these structures after finishing their duties. Later on, John Ellis proposed a new notion of protein folding: the folding and assembly of a certain polypeptide chain to form the correct oligomeric structure is ensured by proteins that act as molecular chaperones. Anfinsen, who considered that all information about the three-dimensional structure of a protein is stored in its amino acid sequence, e.g., a protein could fold itself correctly without external help or impact. The earliest concept of “protein folding” was raised by Christian B. This review systematically illustrated the process of human protein disulfide isomerase (hPDI) mediated disulfide bond formation and complemented this with the current mechanism of wheat protein disulfide isomerase (wPDI) catalyzed formation of gluten networks. Herein, the mechanism of PDI-regulated disulfide bond formation is important for understanding not only protein folding and associated diseases, but also the formation of functional biomolecular assembly. On the other hand, glutenin aggregation and subsequent crosslinking are required for the formation of a rheologically dominating gluten network. Protein misfolding often leads to the formation of pathological protein aggregations that cause many diseases. These domains assist correct folding of proteins, as well as effectively prevent the aggregation of misfolded ones. In eukaryotes, the formation and rearrangement of most intra- and intermolecular disulfide bonds in the endoplasmic reticulum (ER) are mediated by protein disulfide isomerases (PDIs), which consist of multiple thioredoxin-like domains. Moreover, biological molecular assembly, such as the gluten network, is also largely dependent on the intermolecular crosslinking via disulfide bonds. Disulfide bonds play a pivotal role in maintaining the natural structures of proteins to ensure their performance of normal biological functions.
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