Essential Proteins from Neglected Tropical Disease Pathogens - Structural Biology of Infectious Diseases
Diseases caused by pathogens on the WHO's list of neglected tropical diseases (NTDs) affect billions of people worldwide. NTDs are caused by bacteria, viruses or fungi, but the majority stem from parasites. Infections with the single cell protozoan parasiteTrypanosoma brucei spp. lead to African Sleeping Sickness, a fatal disease for humans and their livestock and thus a major health and economic risk. Related parasites such as T. cruzi and Leishmania spp. that hide from the immune system by entering the host's cells, cause tens of millions of cases of Chagas disease (in the Americas) or Leishmaniasis (on five continents).
We study the structures, biophysical properties and inhibtion of essential T. brucei, T. cruzi and leishmania (redox) enzymes, the (dis)similarities of human and parasitic ion channels as well as T. cruzi host cell invasion factors.
Additionally, we are interested in the dynamics and molecular details of (allosteric) inhibition of flaviviral proteases, including the serine protease NS2B-NS3 from Zika and Dengue Virus (another NTD affecting > 300 million globally) required for virus processing and maturation.
- Götz et al (2021) J Phys Chem, accepted
- Johé et al (2021) J Biol Chem, doi: 10.1016/j.jbc.2021.100565
- Johé et al (2021) ACS Chem. Biol., doi: 10.1021/acschembio.0c00911
- Dietschreit, Wagner et al (2020) Angewandte Chemie Int. Ed. Engl.,
- doi: 10.1002/anie.202000539
- Wagner et al (2019) Angewandte Chemie Int. Ed. 58(11):3640-3644. doi: 10.1002/anie.201810470
- Millies et al (2019) J. Med. Chem. 62(24):11359-11382.
- We are very grateful to be supported by a grant from the Helaba together with colleagues from Goethe-University Frankfurt (press releases here, here or here)
- Article based on interview by Eric and Ute on the importance of a holistic approach to NTD research in times of Corona and our support by DFG-GRK 2015 Life Sciences, Life Writing
- Our research into parasitic ion channels is funded by an Exploration Grant of the Boehringer Ingelheim Stiftung, see here (in German)
- The Aventis Foundation, the Fulbright Commission and Angewandte Chemie featured our work on NTDs and the Hoechst Dozentenpreis des Fonds der chemischen Industrie for Ute! (see also JGU Mainz press release, in German)
Transient Receptor Potential (TRP) Ion Channels
Ion channels are responsible that you are able to read this: they make our eyes see, our hearts beat, our neurons communicate, our brains function. Numerous diseases (“channelopathies”) underscore their importance: epilepsy, cystic fibrosis, seizures… (to name only a few) are all caused by dysfunctional ion channels. We are particularly interested in the Transient Receptor Potential (TRP) ion channel superfamily whose members act as temperature and pain sensors and are involved in proper neurodevelopment and maintenance of lysosomal integrity.
Intriguingly, a role for TRP channels in the immune system has been described recently thus positioning these fascinating proteins as an exciting opportunity to explore host-pathogen interactions on a molecular level.
- Goretzki, B. et al (2021) J. Mol. Biol., accepted
- McCray, B., Diehl, E. et al (2021) Nature Commun., accepted
- Viet, K.K., Wagner, A. et al (2019) Structure, 27(8):1246-1257. doi: 10.1016/j.str.2019.04.016.
- Goretzki, B. et al (2018) Structure, 26(12):1583-1593. doi: 10.1016/j.str.2018.08.002
Our structure of the unique Calcium-binding domain of the TRPML2 ion channel featured on the JGU Mainz homepage!
Membrane Proteins in Microbial Communication
Bacterial ABC transporters that can act as multidrug/antibiotic transporters are one of our main research interests. These molecular machines undergo large scale motions to pump amphiphilic molecules that interact with the transmembrane domains out of the cell at the expense of ATP, which interacts with the cytoplasmic nucleotide binding domains. However, the details of these processes remain unclear. We aim for a better understanding of the allosteric pathways of signal propagation through ABC transporter domains and the role of the lipid environment.
ABC transporters are also involved in the transport of microbial peptides and secondary metabolites and thus play essential roles in the way microbes communicate with each other, their environment or with a (human) host!
- FEBS Letters Special Edition (2020)"Diversity of Structure and Function of ABC Transporters", Guest Editors: Amro Hamdoun, Ute A. Hellmich, Karl Kuchler, Gergely Szakacs
- Ford, R. C., Hellmich, U. A. (2020) What monomeric NBDs can teach us about dimeric ABC proteins. FEBS Lett., 594(23):3857-3875
- Rose-Sperling, D., Tran, M. A., Lauth, L.M., Goretzki, B., Hellmich, U.A. (2019) 19F NMR as a versatile tool to study membrane protein structure and dynamics. Biol. Chem., 400(10):1277-1288
- Szöllösi, D., Rose-Sperling, D, Hellmich, U. A., Stockner, T. (2018) Comparison of mechanistic transport cycle models of ABC exporters. Biochim. Biophys. Acta Biomembr. 1860(4):818-832.
- Neumann, J., Rose-Sperling, D. and Hellmich, U. A. (2017) Diverse relations between lipids and ABC transporters: an overview. Biochim. Biophys. Acta Biomembr. 1859(4):605-618.
Ute received the Fulbright-Cottrell Award for our work on bacterial ABC transporters!
Interesting Proteins with Interesting Properties
We are generally fascinated by proteins with interesting structural and dynamic properties, such as the N-terminal domain from spider silk protein whose dynamics and functional but not structural (!) properties are fine-tuned by core methionine residues. Together with the Neuweiler lab in Würzburg, we are now working towards a more detailed understanding of these phenomena using a combination of PET-FCS, NMR spectroscopy and biochemistry.
- Goretzki et al (2020) Biomol NMR Assign. 14:67–71.
- Heiby*, Goretzki* et al (2019) Nature Commun. 10(1):4378.
Our work together with the Neuweiler Lab on the astounding biophysical properties of spider silk was featured in Laborjournal and in German print media, e.g. here, here, here or here. See also the JGU Mainz press release, the press release of the University of Würzburg and the "Behind the paper" view by the Nature Research Chemistry Community
We acknowledge past and present support by:
BMBF - German Federal Ministry of Education and Research
Carl Zeiss Stiftung
Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt funded by the State of Hesse
CONACYT - Consejo Nacional de Ciencia y Tecnologia, Mexico
DAAD - German Academic Exchange Service
DFG - Deutsche Forschungsgemeinschaft, individual grants
DFG EXC 2051 'Balance of the Microverse'
DFG GRK 2015 'Life Science, Life Writing'
EMBO - European Molecular Biology Organization
FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil
FCI - Fonds der chemischen Industrie
FEBS - Federation of European Biochemical Societies
French Embassy in Germany, Dept. for Science and Technology
GBM - Gesellschaft für Biochemie und Molekularbiologie e.V.
GDCh - Gesellschaft Deutscher Chemiker
Hans Böckler Stiftung
Helaba - Landesbank Hessen-Thüringen
Klaus Tschira Stiftung
LOEWE - Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz, Hessen
Mainz University Start-up Funding (Stufe I)
MPGC - Max Planck Graduate Centre
NMFZ - Naturwissenschaftlich-Medizinisches Forschungszentrum
RCSA - Research Corporation for Science Advancement, USA
TransMED - Mainz Graduate School for Translational Medicine