Adaptability, The Achilles Heel Of Gut Bacteria

The ability to switch between oxygen-rich and oxygen-poor environments could also be the downfall of gut bacteria.

AsianScientist (Nov. 20, 2014) – In research published in Nature Chemical Biology, scientists have discovered a surprisingly simple mechanism through which gut bacteria can adjust to the very different oxygen environments inside the human gut.

This research, which was led by Professors Shigeyuki Yokoyama and Wataru Nishii of the Structural Biology Laboratory, opens a new potential target against these bacteria, which are the most-frequently encountered causative microorganisms of infectious diseases. The family includes well-known symbionts and facultative or obligate pathogens such as Escherichia coli, Klebsiella, Salmonella, Shigella and Yersinia pestis.

The team found that a subtle change in an enzyme called Lon, which is involved in the process of proteolysis, allows these bacteria to quickly adapt between the changing oxygen environments inside the gut—where there is practically no oxygen—and outside, where there is plenty.

Proteolysis is an important process through which cells degrade unneeded proteins; it must be tightly controlled to avoid cellular damage. The team discovered a small and surprisingly simple conformational change acts as the switch, allowing the cell to go into a higher proteolysis mode when exposed to an oxygen-rich aerobic environment.

The team used three approaches. First, they analyzed the Lon protease using crystallography and showed that the enzyme can adopt both an oxidized and reduced form. They found that these states could switch in a reversible way, though the formation and reduction of a disulfide bond that caused the exit pore of the enzyme to either widen or narrow. They found that this small change had a dramatic impact on the enzyme’s ability to carry out proteolysis.

Next, they investigated the enzymatic properties of Lon in solution and found that its activity increased in high-oxygen conditions and decreased in conditions such as those in the gut. They identified the change in the exit pore size as the cause of the change.

Finally, they showed that the redox switch actually functions in living cells, demonstrating that cellular Lon activity was low in anaerobic and high in aerobic conditions, carefully regulating the double-edged sword of proteolysis, which can defend cells against external stress but harm them when unnecessary.

According to Dr. Nishii, the first author and one of the two corresponding authors of the studies, “We were very surprised by the fact that a tiny structural change, caused by the bonding and reduction of a single disulfide bond, had such a strong effect on molecular and cellular functions.”

“This is the first example of an ‘allosteric disulfide bond’ that actually regulates the molecular function in normal physiological conditions. Though it remains a target for future investigation, it is an interesting possibility that such mechanisms may also exist in other proteins.”

Schematic of how the enzyme changes in response to varying redox conditions. Credit: RIKEN.
Schematic of how the enzyme changes in response to varying redox conditions. Credit: RIKEN.

Prof. Yokoyama, the other corresponding author, said that the finding was “unexpected”. He hopes that these findings will lead to a new therapeutic target in the fight against infectious diseases.

The article can be found at: Nishii et al. (2014) A Redox Switch Shapes the ​Lon Protease Exit Pore to Facultatively Regulate Proteolysis.


Source: RIKEN.
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