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Oxidative Folding Pathways of Bovine Milk β-lactoglobulin With Odd Cysteine Residues

Oxidative Folding Pathways of Bovine Milk β-lactoglobulin With Odd Cysteine Residues

Michio Iwaoka, Takumi Mitsuji, Reina Shinozaki

FEBS Open Bio. 2019 Aug;9(8):1379-1391.

PMID: 31087497

Abstract:

Bovine β-lactoglobulin (BLG) is a major whey protein with unique structural characteristics: it possesses a free Cys thiol (SH) and two disulfide (SS) bonds and consists of a β-barrel core surrounded by one long and several short α helices. Although SS-intact conformational folding has been studied in depth, the oxidative folding pathways and accompanying SS formation/rearrangement are poorly understood. In this study, we used trans-3,4-dihydroxyselenolane oxide, a water-soluble selenoxide reagent which undergoes rapid and quantitative SS formation, to determine the oxidative folding pathways of BLG variant A (BLGA) at pH 8.0 and 25 °C. This was done by characterizing two key one-SS intermediates, a particular folding intermediate having a Cys66-Cys160 SS bond (I-1) and a particular folding intermediate having a Cys106-Cys119 SS bond (I-2), which have a native Cys66-Cys160 and Cys106-Cys119 SS bond, respectively. In the major folding pathway, the reduced protein (R) with abundant α helices was oxidized to I-1, which was then transformed to I-2 through SS rearrangement. The native protein (N) was formed by oxidation of I-2. The redundant Cys121 thiol facilitates SS rearrangement. N is also generated from an ensemble of folding intermediates having two SS bonds (2SS) intermediates with scrambled SS bonds through SS rearrangement, but this minor pathway is deteriorative due to aggregation or overoxidation of 2SS. During oxidative folding of BLGA, α→β conformational transition occurred as previously observed in SS-intact folding. These findings are informative not only for elucidating oxidative folding pathways of other members of the β-lactoglobulin family, but also for understanding the roles of a redundant Cys thiol in the oxidative folding process of a protein with odd Cys residues.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP9066459	β-Lactoglobulin B from bovine milk		9066-45-9	Price

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