Guiding bar motif of thioredoxin reductase 1 modulates enzymatic activity and inhibitor binding by communicating with the co-factor FAD and regulating the flexible C-terminal redox motif.

Autor:	Shi W; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Sun S; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Liu H; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Meng Y; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Ren K; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Wang G; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Liu M; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Wu J; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Zhang Y; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Huang H; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Shi M; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China., Xu W; School of Ocean Science and Technology (OST) & Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), Dalian University of Technology, Panjin, 124221, China., Ma Q; Chinese Academy of Inspection and Quarantine, Beijing, 100176, China., Sun B; State Key Laboratory of Fine Chemicals, School of Chemical Engineering (CE), Dalian University of Technology, Dalian, 116023, China., Xu J; School of Life and Pharmaceutical Sciences (LPS) & Panjin Institute of Industrial Technology (PIIT), Dalian University of Technology, Panjin, 124221, China. Electronic address: jianqiang.xu@dlut.edu.cn.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Apr; Vol. 70, pp. 103050. Date of Electronic Publication: 2024 Jan 18.
DOI:	10.1016/j.redox.2024.103050
Abstrakt:	Thioredoxin reductase (TXNRD) is a selenoprotein that plays a crucial role in cellular antioxidant defense. Previously, a distinctive guiding bar motif was identified in TXNRD1, which influences the transfer of electrons. In this study, utilizing single amino acid substitution and Excitation-Emission Matrix (EEM) fluorescence spectrum analysis, we discovered that the guiding bar communicates with the FAD and modulates the electron flow of the enzyme. Differential Scanning Fluorimetry (DSF) analysis demonstrated that the aromatic amino acid in guiding bar is a stabilizer for TXNRD1. Kinetic analysis revealed that the guiding bar is vital for the disulfide reductase activity but hinders the selenocysteine-independent reduction activity of TXNRD1. Meanwhile, the guiding bar shields the selenocysteine residue of TXNRD1 from the attack of electrophilic reagents. We also found that the inhibition of TXNRD1 by caveolin-1 scaffolding domain (CSD) peptides and compound LCS3 did not bind to the guiding bar motif. In summary, the obtained results highlight new aspects of the guiding bar that restrict the flexibility of the C-terminal redox motif and govern the transition from antioxidant to pro-oxidant. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier B.V.)
Databáze:	MEDLINE
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