Enzymes play a central role in all metabolic and cellular pathways. Our research team 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 (X-ray crystallography, SAXS), protein engineering, modern biochemistry and detailed steady-state and pre-steady-state kinetics. Moreover, conformational specific Camelidae-derived single domain antibodies (nanobodies) are used throughout as versatile tools to stabilize flexible proteins or subunits from large protein complexes.
Current research topics include the analysis of the structure and function of large multi-domain GTPases and of enzymes involved in tRNA modification.
(Mis)Regulation of complex GTPases in infectious and neurological diseases
Guanine nucleotide binding proteins (GNBPs, G proteins or GTPases) are central “regulatory hubs” in nearly all essential cellular processes. While the small GTPases of the Ras superfamily have been relatively well characterised, the mechanism of complex multi-domain GTPases is much less established. We aim to study the mechanism and regulation of important representatives of these complex GTPases, in the context of bacterial virulence and persistence on the one hand and devastating neurological diseases such as Parkinson disease and epilepsy on the other hand. Insight in the functioning of these proteins and the molecular mechanism behind disease-associated mutations might lead to novel therapeutic strategies on the longer term.
Post-transcriptional tRNA modifications play a primordial role in the translation process as they influence tRNA stability and folding, cognate codon recognition, stabilization of the codon-anticodon wobble base pairing and correct aminoacylation. In the last years, the awareness is growing that post-transcriptional tRNA modifications, especially at the wobble position, might regulate important cellular processes at the level of protein translation. One of our goals is to decipher the structure, function and regulation of these enzyme complexes in order to contribute to our understanding of their cellular roles and the way they are incorporated in signalling networks. In collaboration with the group of L. Droogmans (ULB, Belgium) we are also investigating the structure and function of a variety of methyltransferases in order to get a better understanding of their tRNA specificity and the contribution of their catalytic and RNA-binding domains to catalysis and substrate binding.
- A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover. (Nat Commun, 8, 1008, 2017)
- Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. (Nat Struct Mol Biol, 23, 965-973, 2016)
- Structural and functional insights into tRNA binding and adenosine N1-methylation by an archaeal Trm10 homologue. (Nucleic Acids Res, 44, 940-53, 2016)
- Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts. (Proc Natl Acad Sci U S A, 113, E4357-66, 2016)
- SAXS analysis of the tRNA-modifying enzyme complex MnmE/MnmG reveals a novel interaction mode and GTP-induced oligomerization. (Nucleic Acids Res, 42, 5978-92, 2014)