The molecular basis of neurological disease: structural and mechanistic insights in enzymes and signal transduction pathways implicated in neurological disorders
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MSCA-2020-WVersees01
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Beschrijving van het project
Enzymes play a central role in all metabolic and cellular pathways. The Versées lab therefore focuses on the elucidation of the mechanisms that underlie the tremendous catalytic power and regulation of enzymes and enzyme complexes. To unravel their mechanisms at an atomic level and to understand the way they operate in the context of biological pathways, we use an integrated approach of structural biology methods, protein engineering, biochemistry/biophysics and detailed steady-state and pre-steady-state kinetics. Moreover, conformation-specific Nanobodies are used throughout as versatile tools to stabilize flexible proteins or subunits from large protein complexes.
One strong research focus of our group concerns the regulation and deregulation of enzyme complexes and signal transduction pathways in the context of neurological disorders, such as Parkinson’s disease and epilepsy. Detailed insight in the functioning of these proteins and the molecular mechanism behind disease-associated mutations are subsequently being used to devise new strategies for therapeutic intervention. Projects currently under study include the Parkinson’s disease associated protein LRRK2 and related Roco proteins, TBC1D24 involved in epilepsy and DOORS syndrome and Synaptojanin 1 involved in epilepsy and Parkinson’s disease, while multiple other projects are in a start-up phase.
As a MSCA Fellow you would be hosted in the team of Prof. Wim Versées within the Structural Biology Brussels research group of the Vrije Universiteit Brussel and the VIB-VUB Center for Structural Biology. Our multi-disciplinary center focusses on the structure and dynamics of macromolecular complexes in health and disease. The team of about 100 researchers is housed in new laboratory facilities and combines extensive expertise in structural biology (state of the art in-house cryo-EM, X-ray crystallography, NMR, SAXS, and atomic force microscopy), biophysics, enzymology 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.