Regulation of bacterial toxin-antitoxin systems
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MSCA-22-Loris01
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Beschrijving van het project
The genomes of lost bacteria contain a plethora of small operons commonly referred to as toxin- antitoxin (TA) systems. The toxin typically slows down or almost completely halts bacterial metabolism as a consequence of various kinds of stress such as food limitations. Other proposed functions include protection against bacteriophages, stabilization of chromosomal segments containing non-essential genes and bacterial persistence. Many toxins affect translation by degrading tRNA or mRNA (often in a ribosome-bound context), phosphorylation of elongation factors, or inhibiting gyrase. Under normal growth conditions, the activity of the toxin is inhibited by the antitoxin. In the large group of type II TA systems, both toxin and antitoxin are proteins and the antitoxin inhibits the toxin via the formation of a non-covalent complex. Both toxin and antitoxin also regulate transcription: the antitoxin is a DNA binding protein that acts as repressor. The toxin modifies the DNA binding properties of the antitoxin, often in a ratio-dependent manner.
The Loris group studies the regulation of a number of different TA systems from Escherichia coli as well as pathogenic bacteria such as Vibrio cholerae at the levels of protein activity and transcription. In particular, we want to understand how TA systems respond to stress and correlate in vitro data with in vivo behavior. We wish to find out what mechanisms of regulation are present at the molecular level, with a particular interest in mechanisms that involve functional intrinsic disorder in prokaryotes. Specific projects can be discussed that involve structural biology (X-ray crystallography, NMR and SAXS) combined with protein chemistry (including ITC, CD and mass spectrometry), protein engineering and bacterial in vivo work. You will bring in your own expertise for these techniques but will also be able to acquire fresh skills.
As a MSCA Fellow you would be hosted within the VIB-VUB Center for Structural Biology at the Vrije Universiteit Brussel. This multi-disciplinary center encompasses more than 100 researchers divided over 12 research groups and contains state-of-the-art in-house facilities for protein production, cryo-EM, X-ray crystallography, NMR, SAXS, molecular biophysics and molecular biology.
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Structural Biology Brussels
Structural Biology Brussels (SBB) is headed by Prof. Dr. ir. Jan Steyaert and focusses on research in structural biology. We study the structure of proteins and DNA from the molecular to the atomic level. By determining the position of atoms in a macromolecule (proteins, for example, contain thousands of atoms) we can derive how such molecules can act as tiny machines, and determine how they interact with each other. The end goal of this research is to unravel the complex machinery that makes cells work.
Our work on fundamental aspects of biology and biochemistry also leads to important industrial and biomedical applications. If you know how a protein works, you can also find out why these tiny machines sometimes fail to work as they should. For example, if we learn more about the molecular cause of certain hereditary diseases, or the reason why bacteria can resist antibiotics, then this serves as the first step in rational drug design: developing novel drugs based on knowledge of protein structure and their mode of action.
SBB is a large research groep with about ten principal investigators. This critical mass allows us to employ many complementary state-of-the-art techniques in the field, whose results we combine to obtain a picture of the macromolecules under study that is as accurate and correct as possible. The most important technique we use is X-ray diffraction on protein crystals, as well as NMR spectroscopy, SAXS and electron microscopy. These are supported by our expertise in biochemistry, protein engineering, molecular biophysics and computational structural biology.
At the SBB we also perform fundamental research into the crystallisation and nucleation of biological macromolecules; this goes as far as employing microgravity in the International Space Station.
Finally, the SBB is part of the Structural Biology Research Center (SBRC). The SBRC is part of the Vlaams Instituut voor Biotechnologie (VIB), an institute which encompasses leading research groups with biotechnology interests over the Flemish universities. The aim of the VIB is to translate results from fundamental research in medicine, agriculture and industry.