Bacteria have established various strategies to infect organisms and use
them as sources of nutrients. Many microbes use toxins that break down
membranes by simply piercing through the outer shell of the cells.
Human-pathogenic bacteria such as the plague bacterium Yersinia pestis or other
bacteria from the salmonella family developed a much more subtle mechanism:
they inject their poison by applying a special toxin complex.
A team of researchers led by Stefan
Raunser from the Max Planck Institute of Molecular Physiology in Dortmund has
now been able to fully unveil the sophisticated mechanism using the
bacterium Photorhabdus luminescens as an example.
In most cases, large bio-molecules such as the complex bacterial toxins
cannot be structurally analysed using traditional X-ray crystallography,
because they cannot be converted into the required crystalline state.
Cryo-electron microscopy, however, does not require the samples to be
crystallized. Imaging of even large complexes becomes possible, by freezing
them extremely quickly and examining them directly under the microscope at
minus 196 degrees. Using cryo-EM the team of Stefan Raunser was able to
determine the three-dimensional structure of the Photorhabdus
luminescens toxin for the first time in near-atomic detail. The
structures showed, that the largest subunit of the poison complex, TcA,
resembles a bell, consisting of a channel surrounded by a shell. The upper part
of the bell binds the poison capsule formed by the subunits TcB and TcC.
Receptors on the cell membrane recognize the lower part of the bell and the
loaded poison complex is bound.
Once the pH value of the surrounding medium changes, the outer shell of
the toxin opens up, thus revealing the channel. A protein chain kept under high
pressure then snaps back and pushes the channel through the cell membrane like
the needle of a syringe injecting the poison. The latter is an enzyme which
catalyses the clumping of the cytoskeleton, resulting in the death of the cell.
Molecular gatekeeper
Even today bacterial infections are still among the most frequent causes
of diseases with severe progressions (e.g. sepsis). The intensive use of
antibiotics has led to the development of fatal resistances which have made it
significantly more difficult to win the battle against human-pathogenic
bacteria. Uncovering bacterial infection mechanisms will help to better
understand the mode of action of human-pathogenic bacteria. The newly obtained
insight into the extraordinary mechanism of the Tc-toxin injection could serve
as a starting point for developing innovative therapeutic approaches.
See:
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
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