Research Group Sattler

Molecular recognition in the regulation of gene expression and signaling

A main focus in the Sattler group is to understand the structural basis of protein-RNA interactions that are functionally important for various aspects of gene expression, such as the regulation of (alternative) pre-mRNA splicing and gene silencing by non-coding RNAs (siRNAs, miRNAs). More than 90% of human multi-exon genes are alternatively spliced and misregulation of splicing is linked to various human diseases. The spliceosome is a highly dynamic machinery, which involves numerous protein-RNA interactions. During the different steps that eventually lead to splicing of the pre-mRNA, these complexes are continuously rearranged, and their composition can be modulated, for example in the context of alternative splicing. While this requires that the molecular interactions are dynamic, specific and tight complexes are formed by the cooperative combination of multiple weak protein-protein and protein-RNA interactions. Current projects focus on protein-protein and protein-RNA interactions that play important roles in the regulation of constitutive and alternative splicing and other aspects of RNA metabolism involving non-coding RNAs.

NMR is well suited to study such dynamic and transient interactions in solution. We are implementing and developing integrated structural biology approaches combining NMR-spectroscopy and Small Angle Neutron and/or X-ray Scattering (SAXS/SANS) data with crystallographic and other information to investigate molecular mechanisms involving high molecular weight protein complexes in solution.

Another area of research is structural investigations of proteins and protein complexes involved in different aspects of cellular signaling and peroxisomal biogenesis. Here, we aim to understand the structural basis for critical protein-protein interactions with a focus on proteins that are linked to human disease.

We are also initiating studies for the structure-based design of small molecular inhibitors as i) starting points for pharmaceutical interference and ii) as tools to modulate and monitor cellular signaling. These studies aim at identifying optimized small chemical compounds using structure-guided approaches. NMR is an efficient tool for such a structure-based chemical biology approach since it not only allows to determine the three-dimensional structures in solution but also is efficient in detecting and mapping ligand binding of biomolecules.

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