Research Topics

In-cell NMR spectroscopy

Our reseach projects aims at investigation of the conformation and dynamics of biomolecules under physiologically relevant conditions. In addition, we are developing novel cell mimicking systems allowing fast screening of influence of enviromental factors on biomolecule structure, dynamics and reactivity for pharmaceutical applications.

Chemical signaling

Dominant view in protein chemistry is that the function of a protein is bound to its defined tertiary structure. Recent data, however, indicate that many functional proteins or protein regions lack rigid 3-D structure under physiological conditions, existing instead as dynamic ensembles of inter-converting structures. Latest bioinformatics studies indicate that long natively disordered regions having functional roles are overabundant in proteins (> 70%) involved in cellular signaling. Many oncogenic mutations hit intrinsically disordered regions outside the binding sites for signaling molecules. This suggests that a conformational plasticity of these regions play a key role in transmitting of a chemical signal. The molecular mechanism by which natively unfolded regions participate in transduction of a chemical signal is poorly understood.

We set out to disentangle mechanism of long distance protrusion of a chemical signal through disordered protein region using components of the Wnt signaling cascade as paradigm. This cascade is crucial for development and organogenesis, and its components, containing long natively unfolded regions, are frequent targets for mutation in cancer. Using cutting-edge methods of biochemistry and (in-cell) NMR spectroscopy, we investigate how fundamental signaling events such as non-covalent binding, point mutations, and posttranslational modifications affect conformational plasticity of the natively unfolded regions as well as their propensity to fold under in-vivo conditions.

Mechanistic insight in how chemical signals are transmitted is of vital importance for the design of strategies to interfere with Wnt signaling in cancer. It also provides a rational basis for design of constructs based on natively disordered polypeptides, which act as molecular switches or wires transmitting mechanical impulse over defined distance in nanoscale regime.