Research Group Niessing

Imagine a big city without a car driving and no mail being delivered. The resulting chaos is similar to what happens to a cell when its molecular transport systems are impaired. Our goal is to understand the molecular principles underlying cargo recognition by transport complexes, complex assembly and activation, and eventually complex disassembly after the transport. Our research tools are X-ray crystallography, quantitative biophysical approaches, biochemistry, and in vivo studies.


As a first model, we analyzed the directional transport of ASH1 mRNA in S. cerevisiae. Since then, we expanded our research to neuronal mRNA-protein complexes and their specificity in binding. Two of these neuronal projects involve RNA-binding proteins that have been associated with neuronal disorders:

PURA Syndrome: PURA is an ubiquitously expressed protein with enrichment in the brain. Spontaneous mutations in its gene result in the rare neurodevelopmental disorder PURA Syndrome. We are closely interacting with the patient-centered PURA Syndrome Foundation to understand which molecular and cellular pathways are affected in this disorder and result in the patient's symptoms. Towards this goal, we combine our classical structural and biochemical approaches with cell-culture studies, including iPSC-based analyses, and various omics approaches.

Poly-glutamine diseases: These diseases are caused by pathological genomic expansions of disease-related genes that are translated into polyQ stretches. Proteins with such expanded polyQ stretches tend to form neurotoxic aggregates. Together with our collaboration partners, we are characterizing the therapeutic potential of a novel drug target towards a preventive treatment of affected patients in early stages of their disease.

We are closely interacting with our partner lab at the Ulm University and share our expertise [website].

FIG. 1: ASH1 mRNA transport complex. Taken from Heym & Niessing, Cell Mol Life Sci (2012).

We also study transport factors from neurons. We determined the crystal structure of the neuronal RNA-binding protein Pur-alpha and showed by SAXS that it adopts an unusual topology in solution.
Our long-term goal is to understand how core factors of large multiprotein complexes interact to (i) detect their cargo, (ii) assemble into functional complexes in response to cargo recognition and (iii) translocate their cargo through the cytoplasm. We aim to extend our understanding to transport processes in higher eukaryotes.

 

The X-ray Crystallography Plattform is also built up by our group. It is used for high-resolution structure determination of proteins and co-complexes with other proteins, nucleic acids or small inhibitory molecules.