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Research


Our lab is interested in how bacteria recognize, distribute and employ transition metals, with a particular focus on nickel.  

Through the systems we study, we gain fundamental knowledge about metal-protein interactions, the impact of metals on protein structure and function, and the mechanisms of transition metal homeostasis in living organisms. This information has multiple applications, but in this lab we consider whether these systems could be interrupted, and if so, how this could be achieved as potential antimicrobial strategies.

   

Many transition metals are essential nutrients because they serve as structural and catalytic components of biomolecules, providing unique chemical versatility. However, unregulated accumulation of these elements are toxic and cause a lot of damage to cells. Nature solves this problem by employing specialized metalloproteins that strictly control the availability and distribution of each type of metal. These proteins import metal ions across membranes, deliver the ions to enzymes or sites of storage, sense and control metal availability, as well as detoxify and export the excess.

 

 

Our experiments are designed to address several specific questions:

1.  What are the proteins involved and how do they interact with metals?

2.  How is metal selectivity achieved? 

3.  What is the impact of metals on the protein structure and function? 

4.  What is the mechanism of metal transfer between proteins?

5.  How are the pathways regulated?  How are they integrated within the context of a whole cell or organism?

 

Systems Under Investigation

To address these questions and define the mechanisms of transition metal homeostasis we are studying the proteins from multiple connected nickel pathways, in the context of purified components as well as with live cells. Nickel is essential for many organisms, including a variety of pathogenic bacteria. Two examples of pathogenic bacteria that we study are Escherichia coli and Helicobacter pylori.

The systems that we are investigating include a nickel-responsive transcription factor called NikR, the proteins involved in the biosynthesis of hydrogenase enzymes, a nickel membrane transporter, and a new factor that we identified involved in storage and delivery.

We also develop tools for analyzing metalloproteins and metal availability in cells, and screening methods to identify new components or inhibitors.

 

NikR from H. pylori (PDB: 2CAD)

 

[NiFe]-hydrogenase and active site

 

Techniques

Biological chemistry, and in particular this area of bioinorganic chemistry, is very multidisciplinary.  We use a broad array of techniques from areas such as protein chemistry, molecular biology, biophysical chemistry, inorganic spectroscopy, microbiology, genetics, proteomics, and structural biology.

 

 

 

[NiFe]-hydrogenase and active site from from D. gigas