Research focus

​A deep understanding of the rules governing molecular recognition processes is crucial to the rational design of drugs, and the pharmacological and biotechnological implications are significant. For an in-depth understanding of such processes, elucidation of the complex interrelation between structure, dynamics and energetics becomes essential. Our research is dedicated to understanding this interrelationship by combining structural biology (X-ray crystallography and NMR) with thermodynamics. Our specific interest is in improving the understanding of the fundamentals of biological processes such as protein folding-unfolding-misfolding and protein stability, but particularly that of protein-protein interactions, primarily using high-resolution NMR spectroscopy.
Our group has 3 main research topics:

1. Multiplicity of SH3 domains:
Living cells feature complex protein networks involved in information signal transfer and processing events finely modulated by protein-protein interactions, often mediated by small modular domains such as the SH3 domains. The incidence of different SH3-binding motifs on the same target protein may be an intricate mechanism used by the cell to regulate SH3-mediated interactions. Often, modular interaction domains also occur in tandem on regulatory proteins. The CIN85/CMS family of adaptor proteins contains three highly similar N-terminal SH3 domains that are involved in a wide variety of intermolecular interactions with different targets. It has been hypothesized that such regulatory proteins can increase their affinity and specificity through co-operative binding involving multiple domains of the same or different kinds. The research focuses on the effect of the presence of a second or third domain on the affinity and specificity of the binding to the target. Moreover, recent research has shown that binding affinities change for both the SH2 and the SH3 domain of Fyn when either one of them is already linked to a peptide. Hence, in order to understand domain multiplicity one must also investigate the mechanics of intra- and inter-domain communication. This investigation is performed in collaboration with Tom Lenaerts, former member of the VIB Switch lab, and is a continuation of previous research activities in collaboration with members of the University of Granada. The research objectives also cover the combination of rapid injection techniques with rapid-acquisition NMR methods for the analysis of (fast) kinetic processes.

2. Bacterial toxin-antitoxin (TA) modules (Project leader Remy Loris):
Prokaryotes possess a series of tools to respond to sudden and chronic environmental stresses such as the presence of antibiotics or scarcity of food resources. Among these tools are the so-called toxin-antitoxin (TA) modules, small operons encoding a “toxin” and an “antitoxin” protein. TA toxins recognize their antitoxins via their intrinsically unfolded C-terminal domain, which becomes structured upon binding. These events have to be viewed in the wider perspective of the recognition of intrinsically unstructured binding partners, for which NMR is most suited. Study of the mechanisms and specificity determinants that govern these interactions will therefore also be relevant for the problem of protein folding in general.

3. DBL domains in Malaria (Project leader Stephanie Ramboarina):
Adherence of Plasmodium falciparum-infected erythrocytes to placentas of pregnant women leads to drastic damage and complications during pregnancy (placental malaria). P. falciparum erythrocyte membrane protein 1 (PfEMP1) VAR2CSA protein has been identified as the main adhesin, binding exclusively chondroitin sulfate A (CSA) on the placenta. However, VAR2CSA becomes the target of maternal antibodies after subsequent pregnancies, suggesting that this protein may be an important target of protective immunity and making it the leading candidate for a pregnancy malaria vaccine. VAR2CSA is a large protein of 350 kDa with an extracellular part composed of six Duffy binding-like (DBL) domains of around 36 to 45 kDa. The main goal of this project is to decipher the mechanism of recognition of DBLs of VAR2CSA with glycosaminoglycans, such as CSA.