Researchers in the School of Chemistry at UEA have taken an important step forward in understanding how a group of bacteria that include nitrogen-fixers and important animal pathogens sense the essential micronutrient iron.
Virtually all forms of life require iron to survive and, because of its poor bioavailability, insufficient iron is a common problem, including for humans. At the same time, too much of the metal is harmful. In the living world, many different systems are known to regulate this delicate balance. In many nitrogen-fixing bacteria, a protein called RirA plays a key role in sensing and responding to the availability of iron. It senses low levels of the metal and helps to activate the production of proteins that bring in more iron. RirA contains a cluster of four iron and four sulfur atoms (referred to as [4Fe-4S]), which acts as a sensor for iron availability.
Recent work from the Le Brun group at UEA has revealed much about how this cluster structure detects the levels of the metal in a cell. They showed that one of the four irons can easily come away from the cluster, and, when iron levels drop, this atom is rapidly lost as it is scavenged for use in other essential cellular processes. Without it, the cluster in RirA breaks down and the protein becomes inactive, which prompts the cell to produce proteins that enable the cell to take up iron from its surroundings. Once iron levels are sufficient again, RirA can regain its cluster and is active again, stopping the production of proteins that bring in more iron.
The team, led by Prof Nick Le Brun, which included researchers in the Schools of Chemistry and Biological Sciences at UEA, and collaborators from the John Innes Centre on the Norwich Research Park, and the Institute of Structural Biology in Grenoble, France, have now gained new insight into the RirA cluster and what makes it so fragile. They showed that the substitution of one of the amino acid residue units of the protein by a residue that can bind to the cluster resulted in its stabilisation, such that it was no longer sensitive to low iron conditions. Furthermore, the stabilised form of the protein was locked in its DNA-binding form, and in the bacterial cell, the protein acted as a repressor that was no longer able to sense iron.
Prof Le Brun said: "This research provides novel insight into how the iron sensor RirA functions. We think that the way the cluster is bound to the protein is unusual in that it enables one of the irons to come on and off easily, enabling it to detect iron availability. By changing the cluster binding, we have stabilised that iron, making the cluster ‘blind’ to local iron levels. Thus, we have new understanding of how an iron-sulfur cluster can be used to sense iron, and contributed to solving the bigger puzzle of how life deals with iron, a nutrient it cannot do without but one it must avoid having in excess."
The work was published this week in Chemical Science, DOI: 10.1039/D3SC03020B.
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