The ABC’s of Pathogenic Ferrous Iron Acquisition
The acquisition of iron is an essential process for the establishment of virulence among virtually all pathogens. Under acidic and/or anaerobic conditions, such as those found in the stomach, the intestines, and within biofilms, many pathogens utilize the ferrous iron (Fe2+) uptake (Feo) system to import Fe2+ in order to fulfill their requirement for iron. The Feo system, comprising the proteins FeoA/B/C, is the most widely distributed prokaryotic Fe2+ import pathway, and its presence is required for normal growth of most unicellular organisms. The Feo system is poorly understood at the atomic, molecular, and mechanistic levels, which has prohibited the targeting of this system for bacterial exploits and represents a pressing and urgent gap in the field of bacterial metal homeostasis. While the main membrane component of the Feo system (FeoB) is essential for the translocation of ferrous iron, the small, cytosolic proteins FeoA and FeoC are postulated to function as accessories to this process. However, the exact roles of all three of these proteins remain poorly defined due to a lack of knowledge at the protein level. Previous work from the Smith lab has focused on expression, purification, and characterization of the large and complex membrane protein FeoB. Based on modeling and activity assays, we suggest that ferrous iron import could be driven in an active rather than facilitated manner within the cell through a Met-lined channel. Furthermore, our lab hypothesizes that both FeoA and FeoC govern the regulation of this essential process based on structural, biochemical, and biophysical characterizations of both proteins. These characterizations support a role for nucleotide-mediated FeoA-FeoB interactions, and for the binding of a [4Fe-4S] cluster within FeoC, which may all control Feo function. Thus the Feo system represents a complex but fascinating prokaryotic system dedicated to ferrous iron acquisition under anaerobic and reducing environments, and the implications of our findings will be discussed.