Single-molecule microscopy visualises the dance of receptors
FRANKFURT. Whether a sick cell dies, divides, or travels through the body is regulated by a sophisticated interplay of signal molecules and receptors on the cell membrane. One of the most important molecular cues in the immune system is Tumour Necrosis Factor α (TNFα). Now, for the first time, researchers from Goethe University have visualised the molecular organisation of individual TNFα receptor molecules and the binding of TNFα to the cell membrane in cells using optical microscopy.
Before TNFα can bind to a membrane receptor, the TNFR receptor must first be activated. By doing so, the key will only fit the lock under certain circumstances and prevents, among other things, that a healthy cell dies from programmed cell death. “For TNFR1 in the membrane, the binding of TNFα is mediated through several cysteine-rich domains, or CRDs," explains Sjoerd van Wijk form the Institute for Experimental Cancer Research in Paediatrics and the Frankfurt Stiftung für Krebskranke Kinder at Goethe University.
In particular, CRD1 of the TNFR1 makes it possible for TNFα to “attach". Researchers already knew that TNFR1 molecules cluster in a fashion similar to a dance, in which two, three or more partners grasp hands – with the dimers, trimers or oligomers consisting of single TNFR1 molecules – in the case of TNFR1. This kind of “structural reorganization" also takes place when there is no TNFα present. “Despite the significance of TNFα for many diseases, including inflammation and cancer, the physiology and patterns of TNFR1 in the cell membrane still remain largely unknown up to now," says Sjoerd Van Wijk, explaining the starting point for his research.
In order to understand the processes in the cell membrane in detail, van Wijk approached Mike Heilemann from the Institute for Physical and Theoretical Chemistry at Goethe University. Using a combination of quantitative microscopy and single-molecule super-resolution microscopy that he developed, Heilemann can visualise individual protein complexes as well as their molecular organisation in cells. Together with Ivan Dikic (Institute for Biochemistry II) and Simone Fulda (Institute for Experimental Cancer Research in Paediatrics) from Goethe University, Harald Wajant from the University Hospital Würzburg and Darius Widera from University Reading/UK, they were able to observe the dance of the TNFα receptors. Financial support was provided by the Deutsche Forschungsgemeinschaft (DFG) through the Collaborative Research Centre 807 “Transport and Communication across Biological Membranes".
As the researchers report in the current issue of “Science Signalling", membrane TNFR1 receptors exist as monomers and dimers in the absence of TNFα. However, as soon as TNFα binds TNFR1, receptor trimers and oligomers are formed in the membrane. The researchers also found indications for mechanisms that determine cell fate independently of TNFα. These findings could be relevant for cancer or and inflammatory diseases such as rheumatoid arthritis. “It clearly opens new paths for developing novel therapeutic approaches," states van Wijk.
Publication: C. Karathanasis, J. Medler, F. Fricke, S. Smith, S. Malkusch, D. Widera, S. Fulda, H. Wajant, S. J. L. van Wijk, I. Dikic, M. Heilemann, Single-molecule imaging reveals the oligomeric state of functional TNFα-induced plasma membrane TNFR1 clusters in cells. Sci. Signal. 13, eaax5647 (2020). DOI: 10.1126/scisignal.aax5647
Further information: Dr Sjoerd van Wijk, Institute for Experimental Cancer Research in Paediatrics, Niederrad Campus, Tel.: +49 69 67866574, Email: firstname.lastname@example.org
Prof Mike Heilemann, Institute for Physical and Theoretical Chemistry, Riedberg Campus, Tel.: +49 69 798 29424, Email: email@example.com
In ruminants, a bacterium reacts to fluctuating sodium content with two different respiratory circuits
FRANKFURT. Cows can adapt themselves to a fluctuating sodium content in their feed. How they do that was so far a secret. Researchers from Goethe University have now discovered a bacterium in the microbiome of the rumen which has a new type of cell respiration.
The cow can only process grass in its rumen with the help of billions of microorganisms. An entire zoo of bacteria, archaea and protozoa works there like on a production line: First of all, these single-cell organisms break down the cellulose, a polysaccharide. Other bacteria ferment the sugars released into fatty acids, alcohols and gases, such as hydrogen and carbon dioxide. Finally, methanogenic archaea transform these two gases into methane.
An average cow produces about 110 liters of methane per day. It escapes from its mouth through rumination, but also mixes again with partly digested food. As a result, the sodium content of the grass pulp can fluctuate to a considerable degree (between 60 and 800 millimoles of sodium chloride (NaCLl) per liter).
A German-American research team has now discovered how the ruminal bacteria adapt to these extreme fluctuations in sodium content: “Bioinformatic analyses of the genome of ruminal bacteria led our American colleague Tim Hackmann to assume that some ruminal bacteria have two different respiratory circuits. One of them functions with sodium ions and the other without," explains Professor Volker Müller from the Department of Molecular Microbiology and Bioenergetics at Goethe University. That is why Müller suggested to his doctoral researcher Marie Schölmerich that she study a typical representative in the microbiome of ruminants: the bacterium Pseudobutyrivibrio ruminis.
Together with undergraduate student Judith Dönig and Master's student Alexander Katsyv, Marie Schölmerich cultivated the bacterium. Indeed, they were able to corroborate both respiratory circuits. As the researchers report in the current issue of the Proceedings of the National Academy of Sciences (PNAS), the electron carrier ferredoxin (Fd) is reduced during sugar oxidation. Reduced ferredoxin drives both respiratory circuits.
respiratory circuit comprises the enzyme complex Fd:NAD oxidoreductase (Rnf complex). It
uses energy to transport sodium ions out of the cell. When they re-enter the
cell, the sodium ions trigger an ATP synthase, so that ATP is produced. This
respiratory circuit only works in the presence of sodium ions.
In the absence of sodium ions, the bacterium forms an alternative respiratory circuit with another enzyme complex: The Ech hydrogenase (synonymous: Fd:H+ oxidoreductase) produces hydrogen and pumps protons out of the cell. If these re-enter the cell via a second ATP synthase that accepts protons but not sodium ions, ATP is also produced.
“This is the first bacterium so far in which these two simple, completely different respiratory circuits have been corroborated, but our bioinformatic analyses suggest that they are also found in other bacteria," explains Marie Schölmerich. “It seems, therefore, that this adaptation strategy is more widespread," she assumes.
Interestingly, both enzyme complexes (Rnf and Ech) were also discovered in bacteria which are old in terms of evolutionary biology. Professor Müller's research group has examined them in depth, but always only found one of the two enzyme complexes and never both together. “We're now going to use synthetic microbiology methods to produce hybrids of bacteria that contain both complexes in order to optimize them for biotechnological processes. In this way, we can raise the cellular ATP content, which will make it possible to produce products of a higher quality," explains Professor Müller. The intention is to use the respiratory circuits to recover valuable substances through the fermentation of synthesis gas. This is the subject of the trials being conducted in the framework of a project sponsored by the Federal Ministry of Education and Research.
A picture can be downloaded under: https://www.muk.uni-frankfurt.de/84412971?
Caption: The bacterium Pseudobutyrivibrio ruminis (green), a typical ruminal bacterium, obtains energy via two different respiratory circuits. The one requires sodium ions, the other hydrogen ions (H+). In this way, it can adapt to fluctuating sodium concentrations in animal feed in an optimum way.
Picture: Goethe University/ Cow: Shutterstock
Publication: Schölmerich, M.C., Katsyv, A., Dönig, J., Hackmann, T., Müller, V. (20XX). Energy conservation involving two respiratory circuits. Proc. Natl. Acad. Sci. U.S.A., in press.
Further information: Professor Volker Müller, Molecular Microbiology and Bioenergetics, Riedberg Campus, Tel.: +49(0)69-798-29507; VMueller@bio.uni-frankfurt.de.
With the Centre for Biomolecular Magnetic Resonance, Goethe University is one of 23 European partners in the project iNEXT-Discovery
FRANKFURT. Determining the structure of large biomolecules is critical to many innovations in the fields of health, environment and sustainable technologies. Because structural research requires expensive equipment such as NMR spectrometers, the European Union funds research infrastructure. Beginning in February 2020, an additional € 10 million will be invested in the project iNEXT Discovery. The Centre for Biomolecular Magnetic Resonance (BMRZ) at Goethe University is a part of the project once again.
Currently, the iNEXT Collaboration is made up of 23 partners from 14 European countries. It is the first research infrastructure project combining different structural biological methods: X-ray spectroscopy, nuclear magnetic resonance spectroscopy (NMR), electron microscopy and biophysical methods. These methods make it possible to decode the three-dimensional structure of biological macromolecules in order to understand their function within the complex machinery of life. The goal is to develop new medicines, improved vaccinations, new biomaterials, biofuels, and enzymes for food production.
BMRZ at Goethe University makes its expertise in NMR spectroscopy available to researchers throughout Europe. Visitors from other countries already use the equipment daily to determine the structures of proteins, RNA and DNA. It is furthermore possible for industrial partners to participate via cooperation contracts in order, for example, to search specifically for active substances. Training programmes will be set up in the next four years for researchers with little previous experience with NMR.
“At BMRZ, we give European scientists access to the currently most powerful NMR technologies. In the next funding period, a 1.2 gigahertz NMR spectrometer will be available," says Professor Harald Schwalbe, Board Member of iNEXT-Discovery. “From 2020 onwards, we expect that 20 user groups annually will come from all over Europe to use our equipment and profit from our experience. In this way, we are all contributing to exciting science."
Further information: Professor Harald Schwalbe, BMRZ, Institute for Organic Chemistry and Chemical Biology, Tel.: +49-69-798-29737; Email: firstname.lastname@example.org
Dr Tobias Freimüller receives the Rosl and Paul Arnsberg Prize from the Polytechnic Foundation of Frankfurt am Main
FRANKFURT. Dr Tobias Freimüller, Deputy Director of the Fritz Bauer Institute at Goethe University has been awarded the 2019 Rosl and Paul Arnsberg Prize from the Polytechnic Foundation of Frankfurt am Main. The award, which is given every three years, recognizes outstanding research on the history of Jewish citizens in Frankfurt.
“The work paints a highly differentiated picture of the complex relationships of Jews among themselves and with non-Jewish German society after the Shoah," said the jury, chaired by Professor Mirjam Wenzel, Director of the Jewish Museum and honorary professor at Goethe University, in praise of the winner. Freimüller's work, furthermore, has the potential of becoming a standard work.
Before 1933, Frankfurt am Main had the largest percentage of Jewish citizens in Germany, and its Jewish community was the second largest in Germany following Berlin. In finance, education, science, and through numerous associations and foundations, Jewish citizens influenced the city of Frankfurt in a distinct way. At the end of the war in the spring of 1945, the persecution, deportation and murder of Jews had completely destroyed this diverse culture. Had there once been almost 30,000 Jewish citizens in Frankfurt, now only 100 to 200 remained in the destroyed city.
A larger number of Jewish “Displaced Persons“ (DP) joined the few survivors who had quickly re-founded the Jewish community after the war. These DPs were refugees from Eastern Europe who saw in the American Headquarters in Frankfurt a gateway to their future lives. From here, they hoped to be able to travel to America, Palestine or other countries. But since this path was barred for the time being, thousands of Jewish DPs lived for several years in a hurriedly set-up camp in Frankfurt-Zeilsheim. At the same time, the first Frankfurt Jewish survivors began to return from exile, having been expressly encouraged to do so by Frankfurt's Mayor Walter Kolb.
In his study, Tobias Freimüller depicts how institutions and a social place for Jewish life were gradually able to be established in Frankfurt in the following years. On the one hand, the city serves as a typical example of Jewish post-war history in the Federal Republic of Germany, as a place where the conflict situations of Jewish post-war history can be seen under a magnifying glass. But Frankfurt was also an exception. Under the protection of the American occupying forces, a network of Jewish institutions was quick to form, later including an intellectual scene whose lighthouse was the Institute for Social Research, which had returned from exile. Nonetheless, the relationship between Jewish and non-Jewish citizens in Frankfurt remained particularly conflictive. Highlights of these disputes were the sensational blockade of the premiere of the play "Der Müll, die Stadt und der Tod" by Rainer Werner Fassbinder by the Jewish community in autumn 1985, and the Börneplatz conflict in 1987.
Where, after the end of National Socialism, and in what form did a memory of local Judaism still exist that could be taken up? How should Jewish places of memory that still existed in the city's topography be handled? How did the integration of the Holocaust survivors who fled Eastern Europe after the end of the war succeed, and why did the "second generation" of Jews since the 1960s articulate themselves so clearly in Frankfurt in particular? German-Jewish post-war history appears in the example of Frankfurt as a multi-faceted history of migration, conflict, and new intellectual beginnings, out of which a new Jewish consciousness ultimately developed in the 1980s.
The Rosl and Paul Arnsberg Prize from the Polytechnic Foundation of Frankfurt am Main was created in 2008 and has now been awarded for the sixth time. It is advertised internationally, and is dedicated to outstanding research on the history of Jewish life in Frankfurt. The prize is endowed with € 10,000.
Pictures may be downloaded here: http://www.uni-frankfurt.de/84238080www.uni-frankfurt.de/84238080
Caption: Tobias Freimüller was awarded the Rosl and Paul Arnsberg Prize from the Polytechnic Foundation of Frankfurt am Main for his work on the history of Frankfurt Judaism. (Credit: Polytechnic Foundation of Frankfurt am Main/Dominik Buschardt)
Further information: Dr Tobias Freimüller, Deputy Director of the Fritz Bauer Institute, Goethe University An-Institut, Westend Campus, Tel- +49 69/798 322-31, E-Mail email@example.com, Homepage www.fritz-bauer-institut.de
Archaeologists at Goethe University conclude project in Stockstadt am Main
FRANKFURT. In an extensive project, archaeologists at Goethe University processed and digitally recorded Roman artefacts from Stockstadt am Main (Bavaria). The work lays the groundwork for future research and a new conceptualizing of the museum in Stockstadt.
The Roman Stockstadt is above all internationally known for its Mithras temple (mithraeum), the stone altar of the Beneficiarii (beneficiarii consulares), a kind of military police and customs office for the Roman governor, two bronze faces from paradehelmets of horsemen, and a hoard of coins consisting of 1315 silver coins (denarii). Today, these artefacts are stored and displayed in the Saalburg Museum, the Archaeological Collection of the Bavarian State in Munich, and in the Stiftsmuseum Aschaffenburg.
Extensive excavations were only carried out between 1885 and 1909, and some smaller ones after 1990. Most recently, excavations in the Roman graveyard were conducted in 2011/2012. Since 2005, the Roman site has been a part of the UNESCO World Heritage Site Upper German-Raetian Limes (Obergermanisch-rätischer Limes).
The museums mentioned above are not the only museums storing finds from Stockstadt; the Heimatmuseum Stockstadt possess a collection of more than 6000 objects of Roman artefacts, including diverse objects from daily life and military equipment, but also architectural components from the fort’s fortification and well-preserved burial objects from numerous graves. These finds originate mostly from rescue operations and chance finds at construction sites from the 20th century by volunteers and private citizens, as well as from official excavations. The finds, some of whose are of international significance, are largely unpublished and only exemplarily displayed.
The systematic archiving and indexing of these inventories for science and the interested public was the goal of a Bavarian-Hessian cooperative project involving the city Stockstadt a.M., Goethe University Frankfurt, and the Landesstelle für die nichtstaatlichen Museen in Bayern (State Office for Non-governmental Museums in Bavaria), which was concluded after nine months at the end of 2019. The artefacts are now digitally recorded and researchable according to current standards for cultural assets in a media database of the Landesstelle für die nichtstaatlichen Museen in Bayern. Beginning in 2020, the database will be accessible online through the Stockstadt homepage. To achieve this goal, the artefacts had to be cleaned, sorted according to collection or find site and material, scientifically identified (at least roughly), and dated. In addition, the objects were photographed individually or in groups. This collection and securing of data laid the groundwork for the archiving that accompanied entry of the data into the media database. Each object was labelled with an inventory number.
All of this work was carried out by a small team of students with the support of volunteers. The students thus had the opportunity to gain material knowledge in their area of study and at the same time obtain insight into practical museum work in the digital age. Dr Alexander Reis from Obernburg am Main, who works as scientific assistant at the Institute for Archaeological Sciences (Dept. II) headed the project; his employment was made possible by third-party funding from the city of Stockstadt for this project. He is a specialist in provincial Roman archaeology and received his doctorate at the Goethe University in the Archaeology and History of the Roman Provinces with the thesis “NIDA – Heddernheim in the 3rd Century AD – studies on the end of the settlement” (Manuscripts of the Archaeological Museum Frankfurt 24, Frankfurt a.M. 2010) under Professor Hans-Markus v. Kaenel.
The project has not only yielded an appreciable added value for archaeological Limes research, it also forms the basis for a future reconceptualization of the museum’s permanent exhibit. In the course of the project, it was also possible to transfer the extensive private collection of the local pharmacist Dr Fred Rattinger (1912-1981) to public ownership. The ceremonial transfer of the collection took place on December 2nd as part of a press event.
Pictures can be downloaded here: www.uni-frankfurt.de/83879025
Captions: Picture 1: Sigillata bowl from Gaul, 2nd Century AD; Picture 2: Roman grave from Stockstadt.
Credit: Goethe University
Further information: Professor Markus Scholz, Archeology and History of the Roman Provinces, Institute for Archeological Scineces, Dept. II, Faculty 9, Westend Campus, Tel. +49 (0)69 798 32265, firstname.lastname@example.org