Could E. coli protein lead to new antibiotics?
WASHINGTON U.-ST. LOUIS (US) — New details about how proteins in two bacterial strains delay cell division point to a potential method for designing drugs that stop division entirely.
The two strains—Bacillis subtilis and Escherichia coli—have similar proteins that sample surroundings and sense how much food is available. When food is plentiful, the proteins temporarily block the assembly of constriction rings that pinch cells in two to create two daughter cells.
In 2007 Petra Levin, a biologist at Washington University in St. Louis, reported this findings in Cell regarding the soil bacterium B. subtilis. Now Norbert Hill, a graduate student in her group, reports in PLOS Genetics that E. coli uses a similar protein to help ensure cell size is coordinated with nutrient conditions.
In a rapidly dividing chain of bacterial cells (top), constriction rings that will pinch the cells in two appear in red. The red doughnut to the bottom right of the image is a constriction ring seen head on rather than from the side. In the middle, an image of the constriction rings (red) has been overlaid on one of the cell walls (green), The bottom image shows the constriction rings (red) and the bacterial DNA (blue). (Credit: Levin Lab)
Delaying division even just a little bit leads to an increase in daughter cell size. Once stabilized at the new size, cells take advantage of abundant nutrient sources to increase and multiply, doubling their population at regular intervals until the food is exhausted.
Because both the B. subtilis and E. coli proteins interact with essential components of the division machinery, understanding how they function will help in the discovery of antibiotics that block cell division permanently. A group in Cambridge, England, is already working to crystallize the E. coli protein docked on one of the essential components of the constriction ring.
If they are successful they may be able to see exactly how the protein interferes with the ring’s assembly. An antibiotic could then be designed that would use the same mechanism to prevent division entirely, killing the bacteria.
Getting bigger is complicated
Bacteria increase and multiply by a process called binary fission. Each cell grows and then the divides in the middle to produce two daughter cells. What could be simpler?
But the closer you look, the less simple it becomes.
For binary fission to work the cell must make a copy of its circular chromosome, unlink and separate the two chromosomes to create a gap between them, assemble a constriction ring in the middle of the cell, and coordinate the growth of new cell membrane as the ring cinches tight and pinches the mother cell in two.
To complicate matters, bacteria don’t necessarily do these steps one by one but can instead work on several steps simultaneously.
Most of the time the goal is to produce daughters the same size as the mother cell. But when food is plentiful, bacteria start making more copies of their DNA (as many as 12) in anticipation of divisions to come, and they can’t easily cram all the extra DNA into standard-sized cells.
So they grow bigger to accommodate the extra genetic material and remain large as long as the food lasts.
The inventory of partly copied chromosomes fuels rapid population growth, because a cell doesn’t start from scratch when it needs another copy of its chromosome. Under optimum conditions, E. coli, for example, divides once every 17 minutes. If they are allowed to grow unhindered this means that in 24 hours 1 bacterium becomes about 5 x 1021 bacteria (that is 5 with 21 zeros after it.)
Sample the sugar
In B. subtilis and E. coli the signal is a modified sugar called UDP-glucose. Presumably, the richer the growth medium, the higher the level of this sugar inside the cell.
In both bacteria UDP-glucose binds to a protein and the sugar-protein complex then interferes with the assembly of the constriction ring. In the case of B. subtilis the protein is called UgtP and in the case of E. coli it is OpgH.
“It’s interesting,” Hill says, “that both organisms, which are more different from one another than we are from bakers’ yeast, are using the same system to coordinate changing size in response to nutrient availability.”
UgtP and OpgH are bifunctional proteins that are “moonlighting” as elements of the cell-division control systems. In both cases their day jobs are to help build the cell envelope.
“We think they are communicating not only how much glucose there is in the cell, but also how fast the cell is growing,” Levin says. “The sensor says not only is food abundant, but we’re also growing really fast, so we should be bigger.”
Assemble the ring
Both proteins delay division by interfering with FtsZ, the first protein to move to the division site, where it assembles into a scaffold and recruits other proteins to form a constriction ring.
“Very little is known about the assembly of the ring,” Hill says. “There are a dozen essential division proteins and we don’t know what half of them do. Nor do we understand how the ring develops enough force to constrict.”
“We do know FtsZ exists in two states,” Hill adds. “One is a small monomer and the other is many monomers linked together to form a multi-unit polymer. We think the polymers bind laterally to form a scaffold and then, with the help of other proteins, make a meshwork that goes around the cell.
UgtP and OpgH both interfere with the ability of FtsZ to form the longer polymers necessary for assembly of the constriction ring.
When nutrient levels are low, UgtP and OpgH are sequestered away from the division machinery. FtsZ is then free to assemble into the scaffold supporting the constriction ring so the cell can divide. Because division proceeds unimpeded, cells are smaller when they divide.
What about other bacteria?
This control system helps to explain the observation that bacterial cells get bigger when they are shifted to a nutrient-rich medium.
Comparing the mechanisms that govern cell division in E. coli and B. subtilis reveals conserved aspects of cell size control, including the use of UDP-glucose, a molecule common to all domains of life, as a proxy for nutrient availability, and the use of moonlighting proteins to couple growth-rate-dependent phenomena to the central metabolism.
But much more is known about these model organisms, which many labs study, than the average bacterium. Nobody is sure how many species of bacteria there are—somewhere between 10 million and a billion at a guess—and they don’t all divide the way B. subtilis and E. coli do.
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