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Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR.

ABSTRACT: Quinone molecules are intracellular electron-transport carriers, as well as critical intra- and extracellular signals. However, transcriptional regulation of quinone signaling and its molecular basis are poorly understood. Here, we identify a thiol-stress-sensing regulator YodB family transcriptional regulator as a central component of quinone stress response of Staphylococcus aureus, which we have termed the quinone-sensing and response repressor (QsrR). We also identify and confirm an unprecedented quinone-sensing mechanism based on the S-quinonization of the essential residue Cys-5. Structural characterizations of the QsrR-DNA and QsrR-menadione complexes further reveal that the covalent association of menadione directly leads to the release of QsrR from operator DNA following a 10° rigid-body rotation as well as a 9-Å elongation between the dimeric subunits. The molecular level characterization of this quinone-sensing transcriptional regulator provides critical insights into quinone-mediated gene regulation in human pathogens.

SUBMITTER: Ji Q

PROVIDER: S-EPMC3612684 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR.

Ji Quanjiang Q Zhang Liang L Jones Marcus B MB Sun Fei F Deng Xin X Liang Haihua H Cho Hoonsik H Brugarolas Pedro P Gao Yihe N YN Peterson Scott N SN Lan Lefu L Bae Taeok T He Chuan C

Proceedings of the National Academy of Sciences of the United States of America 20130311 13

Quinone molecules are intracellular electron-transport carriers, as well as critical intra- and extracellular signals. However, transcriptional regulation of quinone signaling and its molecular basis are poorly understood. Here, we identify a thiol-stress-sensing regulator YodB family transcriptional regulator as a central component of quinone stress response of Staphylococcus aureus, which we have termed the quinone-sensing and response repressor (QsrR). We also identify and confirm an unpreced ...[more]

PMID: 23479646

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Project description:BackgroundExcitotoxicity plays a key role in nervous system disease and can trigger a critical cascade of reaction which affects cell viability and promotes neuronal death. Tetramethylpyrazine (TMP) reveals its effect in the treatment of neurovascular diseases by antiapoptosis. Recently, there were several studies that demonstrated that the PKA/CREB signaling pathway played a role in neural disease because of excitotoxicity, such as stroke, AD, and Parkinson's disease. In this study, we wanted to focus on the protective effect of tetramethylpyrazine against excitotoxicity through the PKA/CREB signaling pathway.MethodsIn order to verify whether tetramethylpyrazine can attenuate excitotoxicity through the PKA/CREB signaling pathway, we first used molecular docking technology to predict the combinational strength and mode of tetramethylpyrazine with the proteins in the PKA/CREB signaling pathway. Then, we determined the optimal concentration and time according to the model effect of glutamate (Glu) with different concentration gradients and action times in PC12 cells. After the determination of concentration and time of glutamate in the previous step as the model way, tetramethylpyrazine was added to determine its influence on the cell viability under different doses and times. The TUNEL assay and flow cytometry were used to detect apoptosis. RT-PCR was used to detect the expression of Bcl-2, Bax, PKA, and 5CREB genes, and Western blot was used to detect the expression of these factors.ResultTetramethylpyrazine had a good docking score (-5.312) with PKA and had a moderately docking score (-3.838) with CREB. The CCK-8 cell activity assay showed that the activity of PC12 cells decreased gradually with the increase in glutamate concentration and time, and PC12 cells were treated with 10 mM/L glutamate (the half of the inhibitory concentration (IC50)) for 12 hours. Then, the cell viability increased gradually following the increased concentration of tetramethylpyrazine. When PC12 cells were treated with 0.1 mM/L tetramethylpyrazine, the cell viability was increased significantly compared with the control group (P < 0.05). The TUNEL assay and flow cytometry also showed that tetramethylpyrazine could decrease the apoptosis induced by glutamate. In the result of RT-PCR, the transcriptional levels of Bcl-2, PKA, and CREB were increased and Bax was decreased. Meanwhile, Western blot showed that expression levels of Bcl-2, PKA, CREB, and p-CREB were increased and Bax was decreased.ConclusionsThis study provided evidence that tetramethylpyrazine can protect against apoptosis caused by neuroexcitotoxicity and the protective mechanism is closely related to the activation of the PKA/CREB signaling pathway.

Dataset Information

Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR.

Publications

Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR.

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