Enzymatic and synthetic regulation of polypeptide folding

Muraoka, Takahiro; Okumura, Masaki; Saio, Tomohide

doi:10.1039/d3sc05781j

Cited by 5 publications

(3 citation statements)

References 132 publications

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“…Besides cellular protein folding by cytosolic chaperones, many nascent polypeptides are inserted into the endoplasmic reticulum (ER), where oxidative folding, coupled with disulfide bond formation occurs. More than 20 members of the protein disulfide isomerase (PDI) family are known to function in the ER as both chaperones and disulfide bond-catalysts [6][7][8][9] . Although PDI family members have different amino acid sequences, they all contain at least one thioredoxin (Trx)-like domain with or without a redox active CxxC motif, and the three-dimensional arrangements of these Trx domains are distinct from one another, resulting in different functionalities 7,[9][10][11][12][13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Client recognition differences between PDI and ERp46 to guide oxidative folding

Saio,

Ishii,

Matsusaki

et al. 2024

Preprint

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Endoplasmic reticulum (ER)-resident protein disulfide isomerase (PDI) family members function not only as disulfide bond-catalysts but also as chaperones for the oxidative folding of client proteins. However, due to the scarcity of structural data, the client recognition mechanism remains poorly understood. We report the distinct recognition mechanisms for PDI/ERp46 proteins to recruit a reduced and denatured bovine pancreatic trypsin inhibitor (BPTI). NMR data demonstrated that PDI recognizes a broad region consisting of ~30 amino acid residues in unfolded BPTI in order to function as a chaperone, while ERp46 interacts nonspecifically and weakly with unfolded BPTI to promiscuously and rapidly introduce disulfide bonds. These two distinct client recognition modes are likely important for the functional modulation of the disulfide-catalyst and chaperone against client proteins. Client recognition differences between PDI family proteins likely contribute to determining whether disulfide bonds are introduced into the client protein or aggregates are reduced to an unfolded state during the early folding step. Thus, the mammalian ER ensures concerted protein quality control through the differences in the client recognition modes of PDI family proteins, resulting in the production of large quantities of multiple-disulfide bonded proteins.

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Section: Introductionmentioning

confidence: 99%

Client recognition differences between PDI and ERp46 to guide oxidative folding

Saio,

Ishii,

Matsusaki

et al. 2024

Preprint

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“…Notably, redox active site dysfunction in PDIA1 and PDIA6 CxxC motifs induced by posttranslational chemical modifications has been observed in AD, 6 suggesting that misfolding-related pathologies can be ameliorated using redox chemistry. 7…”

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confidence: 99%

“…Further, dysfunction of PDI family members is known to cause pathological diseases such as neurodegeneration and diabetes. 4,7 Therefore, chemically controlling the PDI family as ER-resident redox enzymes is crucial.…”

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confidence: 99%

Boosting the enzymatic activity of CxxC motif-containing PDI family members

Kuramochi,

Yamashita,

Arai

et al. 2024

Chem. Commun.

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ER Oxidoreductin 1‐Like Activity of Cyclic Diselenides Drives Protein Disulfide Isomerase in an Electron Relay System

Mikami,

Nishizawa,

Iwata

et al. 2024

ChemBioChem

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Disulfide formation generally involves a two‐electron oxidation reaction between cysteine residues. Additionally, disulfide formation is an essential post‐translational modification for the structural maturation of proteins. This oxidative folding is precisely controlled by an electron relay network constructed by protein disulfide isomerase (PDI), with a CGHC sequence as the redox‐active site, and its family enzymes. Creating reagents that mimic the functions of these enzymes facilitates folding during chemical protein synthesis. In this study, we aimed to imitate a biological electron relay system using cyclic diselenide compounds as surrogates for endoplasmic reticulum oxidoreductin 1 (Ero1), which is responsible for the re‐oxidation of PDI. Oxidized PDI (PDIox) introduces disulfide bonds into substrate proteins, resulting in its conversion to reduced PDI (PDIred). The PDIred is then re‐oxidized to PDIox by a coexisting cyclic diselenide compound, thereby restoring the function of PDI as a disulfide‐forming agent. The produced diselenol state is readily oxidized to the original diselenide state with molecular oxygen, continuously sustaining the PDI catalytic cycle. This artificial electron relay system regulating enzymatic PDI function effectively promotes the oxidative folding of disulfide‐containing proteins, such as insulin—a hypoglycemic formulation—by enhancing both yield and reaction velocity.

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Enzymatic and synthetic regulation of polypeptide folding

Abstract: This perspective focuses on the latest understanding of the folding-promotion mechanisms by chaperones and oxidoreductases and recent progress in the development of chemical mimics that possess activities comparable to enzymes.

Cited by 5 publications

References 132 publications

Client recognition differences between PDI and ERp46 to guide oxidative folding

Client recognition differences between PDI and ERp46 to guide oxidative folding

Boosting the enzymatic activity of CxxC motif-containing PDI family members

ER Oxidoreductin 1‐Like Activity of Cyclic Diselenides Drives Protein Disulfide Isomerase in an Electron Relay System

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