Pathogenic
bacteria develop killer machines that work very specifically and highly
efficiently. Scientists from the University of Freiburg have solved the
molecular mechanism of a fish toxin that could be used in the future as
a medication to treat cancer. The scientists have now published their
research in the journal Nature Communications.
The
Yersinia species of pathogens can cause the bubonic plague and serious
gastrointestinal infections in humans. The pharmacologist Dr. Thomas
Jank and his fellow researchers in the research group led by Prof. Dr.
Dr. Klaus Aktories at the University of Freiburg studied a pathogen of
the Yersinia family (Yersinia ruckeri). This pathogen causes redmouth
disease in Salmonidae, which includes salmon and trout, resulting in
large financial losses in the fish industry. The research group was able
to identify a toxin injection machine in the Y. ruckeri genome. The
structure of this machine resembles that of viruses that normally attack
bacteria. The group demonstrated that the toxin Afp18 in this injection
machine is an enzyme that deactivates the switch protein RhoA. RhoA is
responsible for many vital processes in the cells of humans and fish.
For example, it controls the building up and breaking down of actin
filaments. These filaments are not only necessary for cell division, but
also for the spreading of tumour metastases in the body.
In
close collaboration with the developmental biologist Prof. Dr. Wolfgang
Driever, also from the University of Freiburg, the research group
injected the toxin Afp18 into zebra fish embryos. The result was that
cell division was blocked, and the fish embryos did not develop. The
toxin caused the actin filaments in the fish cells to collapse. This is
because the Afp18 attaches a sugar molecule, an N-acetylglucosamine,
onto the amino acid tyrosine in RhoA. According to the scientists, this
is a very unusual reaction in nature. The team was able to shed light on
this mechanism at the atomic level through the X-ray analysis of
Afp18-modified RhoA crystals. For this, they collaborated with Prof. Dr.
Daan von Aalten from the University of Dundee, Scotland. Rho-regulatory
proteins are involved in the growth of cancer, especially metastasis.
For this reason, the researchers from the University of Freiburg believe
that this fish toxin has great therapeutic potential in cancer
treatment.
Thomas
Jank and Klaus Aktories are researchers at the Institute of
Experimental and Clinical Pharmacology and Toxicology at the University
of Freiburg. Wolfgang Driever is the head of the Department of
Developmental Biology of the Institute of Biology I, also at the
University of Freiburg. Both Aktories and Driever are members of the
cluster of excellence BIOSS Centre for Biological Signalling Studies.
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