Oral Presentation The 42nd Lorne Conference on Protein Structure and Function 2017

The structural basis of bacterial iron piracy from host ferredoxin (#37)

Rhys Grinter 1 , Inokentijs Josts 2 , Aleksander W Roszak 3 , Alexandre M J J Bonvin 4 , Daniel Walker 3 , Trevor J Lithgow 1
  1. Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria, Australia
  2. Biochemistry, University of Hamburg, Hamburg, Germany
  3. University of Glasgow, Glasgow, United Kingdom
  4. Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, Netherlands

Gram-negative bacterial pathogens are highly significant infectious agents of humans and animals. They are responsible for epidemic diseases like bubonic plague (Yersinia pestis), cholera (Vibrio cholerae), typhoid (Salmonella Typhi), and dysentery (Shigella spp.) as well as numerous other infections.  

To prevent microbial infection, the mammalian host tightly sequesters iron in specialized proteins. This sequestration constitutes a key first line of defense in our innate immune system and is termed ‘nutritional immunity’ (1). To overcome this barrier to infection Gram-negative bacterial pathogens have evolved outer membrane receptors which specifically target host iron containing proteins. In specialized human pathogens, like the casual agents of meningitis and gonorrhea (Haemophilus influenza and Neisseria gonorrhoeae), these proteins target a variety of substrates including transferrin and hemoglobin. These receptors are necessary and sufficient to provide iron for growth of these pathogens during infection (2, 3).

Despite considerable research into iron-uptake systems from Gram-negative pathogens, we still lack a complete picture of their diversity and significance during infection. In this work we report the discovery of FusA, a new family of receptor, which we show targets the small iron containing protein ferredoxin. To determine how FusA targets host ferredoxin we have solved the crystal structure of FusA and its ferredoxin substrate. Then, combining this structural data with NMR driven molecular docking simulations, we show that binding of ferredoxin occurs through highly specialised extra-cellular loops, which form extensive interactions with the small globular ferredoxin. The function of FusA and its presence in numerous clinically important human pathogens shows for the first time that small iron containing proteins represent an iron source to the invading bacterial pathogen (4). This work improves our understanding of the diversity of strategies employed by bacteria in obtaining iron from their hosts, and in doing so provides a means of combating bacterial infection.

  1. James E. Cassat, Eric P. Skaar, Iron in Infection and Immunity. Cell Host Microbe 13, 509-519 (2013).
  2. N. Noinaj et al., Structural basis for iron piracy by pathogenic Neisseria. Nature 483, 53-58 (2012).
  3. C. N. Cornelissen et al., The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers. Mol. Microbiol. 27, 611-616 (1998).
  4. R. Grinter et. al., Structure of the bacterial plant-ferredoxin receptor FusA. Nature Communications, In press