Research interests

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Biogenesis of iron-sulfur proteins

Iron-sulfur clusters are ubiquitous.  They have become integral parts of diverse physiological processes including energy conversion, nitrogen fixation, photosynthesis, intracellular iron homeostasis, biosynthesis of heme, biotin and lipoic acid, RNA modification, amino acid synthesis, protein translation, DNA replication and repair, and gene expression regulation. Throughout evolution, organisms have developed a set of highly conserved proteins that are dedicated for the iron-sulfur cluster assembly in proteins. Deletion of the iron-sulfur cluster assembly proteins is lethal to organisms, and deficiency of iron-sulfur cluster assembly has been attributed to a number of human diseases such as muscle fatigue and Friedreich's ataxia. Using Escherichia coli as a model system, we aim to illustrate how iron and sulfide are delivered in concert for the iron-sulfur cluster assembly in target proteins.

Recent publications:

Yang, J., Tan, G., Zhang, T., White, R. H., Lu, J., & Ding H. (2015) Deletion of the proposed iron chaperones IscA/SufA results in accumulation of a red intermediate cysteine desulfurase IscS in Escherichia coli. J. Biol. Chem. 290, 14226-14234.

 

Tan, G., Cheng, Z., Peng, Y., Landry, A. P., Lu, J., & Ding, H. (2014) Copper binding in IscA inhibits iron-sulphur cluster assembly in Escherichia coli. Mol. Microbiol. 93,629-644.

 

Cheng, Z., Tan, G., Wang, W., Su, X., Landry. A. P., Lu, J., & Ding, H. (2014) Iron and Zinc Binding Activity of Escherichia coli Topoisomerase I Homolog YrdD. Biometals, 27, 229-236.

Landry, A. P., Cheng, Z., & Ding, H. (2013) Iron binding is essential for the function of IscA in iron-sulfur cluster biogenesis. Dalton Trans. 42, 3100-3106.

 

Wang W, Huang H, Tan G, Si F, Liu M, Landry AP, Lu J, Ding H. (2010) In vivo evidence for the iron binding activity of an iron-sulfur cluster assembly protein IscA in Escherichia coli. Biochem. J. 432, 429-436.

Redox regulation of iron-sulfur proteins

Reduction/oxidation of iron-sulfur clusters in proteins may lead to subtle conformational change and subsequently modulate specific activity of the protein.  For example, the E. coli DNA-damage-inducible DNA helicase DinG hosts [4Fe-4S] cluster. We demonstrated that DinG with a reduced [4Fe-4S] cluster is inactive, and that the DNA helicase activity of DinG is switched on when the reduced [4Fe-4S] clusters is oxidized by hydrogen peroxide. A recent example is the human mitochondrial outer membrane protein mitoNEET which contains a [2Fe-2S] cluster via unusual ligand arrangement of three cysteine and one histidine residues.  Our research has revealed that the mitoNEET [2Fe-2S] cluster can be reduced by biological thiols and oxidized by hydrogen peroxide, suggesting that mitoNEET may act as a novel sensor to oxidative signals to regulate energy metabolism in mitochondria. The goal of this project is to establish molecular mechanisms for redox regulation of iron-sulfur proteins in response to oxidative signals.

Recent publications:

Landry, A. P., Cheng, Z., & Ding, H. (2015) Reduction of mitochondrial protein mitoNEET [2Fe-2S] clusters by human glutathione reductase.  Free Radic. Biol. Med. 81, 119-127.

 

Landry, A. P., & Ding, H. (2014) Redox Control of Human Mitochondrial Outer Membrane Protein MitoNEET [2Fe-2S] Clusters by Biological Thiols and Hydrogen Peroxide. J. Biol. Chem. 289, 4307-4315.

 

Tan, G., Landry, A. P., Dai, R., Wang, L., Lu, J., & Ding, H. (2012) Competition of zinc ion for the [2Fe-2S] cluster binding site in the diabetes drug target protein mitoNEET. Biometals. 25, 1177-1184.

 

Cheng, Z., Caillet, A., Ren, B., & Ding, H. (2012) Stimulation of Escherichia coli DNA damage inducible DNA helicase DinG by the single-stranded DNA binding protein SSB. FEBS Lett. 586, 3825-3830.

 

Ren, B. Duan, X. & Ding, H. (2009) Redox control of the DNA damage-inducible protein DinG helicase activity via its iron-sulfur cluster.  J. Biol. Chem. 284, 4829-4835.

 

Nitric oxide cytotoxicity and iron-sulfur proteins

Nitric oxide (NO) produced in activated macrophages and neutrophils may act as a powerful weapon to kill pathogenic bacteria and tumor cells.  An excessive production of NO has also been implicated in causing neurodegenerative disorders, cardiovascular diseases, and cancers.  However, specific targets of NO have not been fully understood.  Recent studies have suggested that iron-sulfur clusters are the primary target of NO in bacterial cells.  When cells are exposed to NO, a large number of iron-sulfur proteins are modified forming the protein-bound dinitrosyl iron complexes, resulting in a prolonged bacteriostasis.  Our research has been focusing on the redox reactions underlying the NO-mediated modifications of iron-sulfur proteins and the cellular mechanisms for repairing the NO-modified iron-sulfur proteins.

Recent Publications:

Landry, A. P. & Ding, H. (2014) The N-terminal domain of human DNA helicase Rtel1 contains a redox active iron-sulfur cluster. Biomed Res Int. 2014:285791.

 

Landry, A. P., Duan, X., Huang, H., & Ding, H. (2011) Iron-sulfur Proteins Are the Major Source of Protein-bound Dinitrosyl Iron Complexes Formed in Escherichia coli Cells under Nitric Oxide Stress. Free Radic. Biol. Med. 50, 1528-1590.

Yang, J., Duan, X., Landry, A. P. & Ding, H. (2010) Oxygen is required for the L-cysteine-mediated decomposition of the protein-bound dinitrosyl iron complexes.  Free. Radic. Biol. Med. 49, 268-274.

Duan, X., Yang, J., Ren, B., Tan, G.& Ding, H. (2009) Reactivity of nitric oxide with the [4Fe-4S] cluster of dihydroxyacid dehydratase from Escherichia coli. Biochem. J.  417, 783-789.

 

Ren, B., Zhang, N, Yang, J.& Ding, H. (2008) Nitric oxide-induced bacteriostasis and modification of iron-sulphur proteins in Escherichia coli Mol. Microbiol. 70, 953-964.