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Research Summary

The aim of our studies is to understand the structural and dynamical adaptions of molecular machines at the atomic level to be able understand their functionality. We study essential cellular processes whose dysfunction and/or dysregulation are often at the basis of a plethora of different diseases like cancer or neurodegenerative disorders. Subsequently, we plan to use our structural and functional knowledge for the possible future development of new antibiotics and drugs for the associated diseases.

Protein Quality Control

The majority of proteins depend on a well-defined three-dimensional structure to obtain their functionality. In the cellular environment, the process of protein folding is guided by molecular chaperones to avoid misfolding, aggregation, and the generation of toxic species. To this end, living cells contain complex networks of molecular chaperones, which interact with substrate polypeptides by a multitude of different functionalities: transport them towards a target location, help them fold, unfold misfolded species, resolve aggregates, or deliver them towards a proteolysis machinery. Together this system is termed protein quality control (PQR). Owing their dynamical adaptions to be able interact with a wide-range of clients molecualr chaperones are an ideal target to be studies by high-resolution NMR-spectroscopy (Burmann & Hiller, Prog. NMR Spect. 2015). Initial studies on bacterial holdase chaperones revealed a unique interaction mode for the interaction between chaperones and its clients based on avidity and re-orientation of the client on the chaperone surface whereas the client is kept in a folding competent dynamic “fluid-globule” state (Burmann et al., NSMB 2013). Subsequently, a combination of single-molecule force spectroscopy (SMFS) and NMR spectroscopy was employed to characterize how the periplasmic holdase chaperones SurA and Skp shape the folding trajectory of the large β-barrel Omp FhuA from E. coli (Thoma et al., NSMB 2015). The ATP-independent chaperones SurA and Skp prevent unfolded FhuA polypeptide from misfolding by stabilizing a dynamic state, allowing a search for structural intermediates. Ongoing and future work will be dedicated to the detailed study how ATP-dependent unfoldases and proteases recognize and unfold their target proteins. Especially, how these molecular machines are able to dissolve protein fibrils and large aggregates, which are often found in Neurodegenerative diseases, will be studied at the atomic level.

Transcription Coupled Repair

Bacterial transcription, the production of an RNA transcript from a DNA template, is performed by the RNA polymerase (RNAP). Previous work on a class of transcription factors making RNAP pause-resistant revealed the existence of a direct linkage between transcription and translation machinery, or the RNAP and the ribosome (Burmann et al., Science 2010; Burmann et al., Cell 2013). This work showed the direct connection between different essential machineries in the cell.
In addition RNAP is also directly involved in cell maintenance functions: RNAP functions as a global sensor of DNA-damages subsequently recruiting the DNA-repair machinery, a process termed transcription-coupled repair (TCR) (reviewed in Belogurov & Artsimovitch Annu. Rev. Microbiol. 2015). Ongoing and future work will be dedicated to the detailed study how the repair proteins are recruited to the DNA damage site and how they either disassemble the RNAP or restart it after successful DNA-repair. These studies might open new leads for the design of new antibiotics targeting new important sites on RNAP or other components of the TCR-machinery.

Integrated Structural Biology Approaches

To study our systems of interest we make mainly use advanced high-resolution NMR-spectroscopy. We have direct access to the Swedish NMR Centre on-site here in Gothenburg, enabling our challenging studies of large protein complexes. In this regard we also plan to further develop and optimize the NMR-methodology for studying these large and complex systems. In order to study the whole functionality of the systems, we employ a comprehensive combination of structural biology techniques besides NMR-spectroscopy, including X-ray crystallography and electron microscopy at state-of-the-art level to obtain atomic resolution representations of the architecture of large protein assemblies. Further we combine our studies with extensively biophysical characterizations to study interactions and structural adaptions.

Page Manager: Mattias Lindgren|Last update: 4/21/2017

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