D 5 - Roland Lill & Ulrich Mühlenhoff

Sensing and intracellular delivery of iron by fungal monothiol glutaredoxins


Roland Lill   
    

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Prof. Dr. Roland Lill

Philipps-Universität Marburg,
Faculty of Medicine 

Robert-Koch-Straße 6,
35037 Marburg

+49 - 6421 - 2866449

lill@staff.uni-marburg.de

http://www.uni-marburg.de/fb20/cyto

        

  Ulrich Mühlenhoff   


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PD Dr. Ulrich Mühlenhoff

Philipps-Universität Marburg,
Faculty of Medicine 

Robert-Koch-Straße 6,
35037 Marburg

+49 - 6421 - 2864171

muehlenh@staff.uni-marburg.de

http://www.uni-marburg.de/fb20/cyto

 

Research summary:

Iron is both an essential and at elevated levels toxic trace element, yet its bioavailability is low. Accordingly, fungal organisms have developed diverse strategies to acquire adequate amounts of the metal to satisfy their metabolic needs and to avoid iron overloading. We previously found that cytosolic multi-domain monothiol glutaredoxins bind a glutathione-coordinated [2Fe-2S] cluster that plays an important role as a sensor in the regulation of cellular iron homeostasis. Moreover, these proteins perform a central, yet poorly defined role in the biogenesis of cytosolic and nuclear iron sulfur proteins. Finally, monothiol glutaredoxins were found to be essential for the insertion of iron into the diferric-tyrosyl radical cofactor of ribonucleotide reductase and into other metalloenzymes. How monothiol glutaredoxins fulfil their diverse physiological functions remains unclear.

Our recent studies indicate that they do not simply function as an iron donor because we identified several cytosolic iron-sulfur proteins that are matured without these glutaredoxins. A central goal of this project will be the mechanistic elucidation of the molecular function of these glutaredoxins in iron uptake regulation, intracellular iron distribution, cytosolic-nuclear iron-sulfur protein biogenesis, and maturation of ribonucleotide reductase and other iron-binding proteins. To this end, we will employ in vivo and in vitro approaches to identify and characterize new interaction partners, explore their role in cytosolic-nuclear iron-sulfur protein biogenesis and in intracellular iron distribution, analyze whether the [2Fe-2S] cluster is transiently or permanently bound to the proteins, address whether they act as apo-monomers or holo-dimers, and identify a potential enzymatic (redox) function of these interesting and important proteins. When needed, we will compare the function of the cytosolic monothiol glutaredoxins with their mitochondrial counterparts, and we will comparatively study the function of these proteins in human cells.