Clustering of receptors can have the same effect as binding a signaling molecule – receptor clusters can direct cell movement
Whether we smell, taste or see, or when adrenaline rushes through our veins, all of these signals are received by our cells via a specific group of receptor proteins called G protein-coupled receptors, which transmit signals to the inside of the cell. Biochemists at Goethe University Frankfurt and the University of Leipzig have now discovered that such receptors can also produce signals even in the absence of an external stimulus: It is apparently sufficient for certain receptors if many of them are clustered at the cell surface. (Science, doi/10.1126/science.abb7657)
FRANKFURT. Our body consists of 100 trillion cells that communicate with each other, receive signals from the outside world and react to them. A central role in this communication network is attributed to receiver proteins, called receptors, which are anchored at the cell membrane. There, they receive and transmit signals to the inside of the cell, where a cell reaction is triggered.
In humans, G protein-coupled receptors (GPC receptors) represent the largest group of these receptor molecules, with around 700 different types. The research of the Frankfurt and Leipzig scientists focused on a GPC receptor that serves as a receptor for the neuropeptide Y in cells and is accordingly called the Y2 receptor. Neuropeptide Y is a messenger substance that primarily mediates signals between nerve cells, which is why Y2 receptors are mainly present in nerve cells and among other activities trigger the formation of new cell connections.
In the laboratory, the researchers engineered cells, which had approx. 300,000 Y2 receptors on their surface and were grown on specifically developed, light-sensitive matrices. Each of the Y2 receptors was provided with a small molecular "label". Once the scientists created a spot of light with a fine laser beam on the cell surface, the Y2 receptor under this spot were trapped via the molecular label to the exposed matrix in such a way that the Y2 receptors moved closely together to form an assembly known as a cluster. The whole reaction could be immediately observed at the defined spot and within a few seconds.
Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt
explains: "The serendipity about this experiment is that the clustering of
receptors triggers a signal that is similar to that of neuropeptide Y. Solely
by the clustering, we were able to trigger cell movement as a reaction of the
cell. The laser spots even allowed us to control the direction of the cell
movement." As the light-sensitive lock-and-key pairs utilized are very
small compared to the receptors, the organization of the receptors in the cell
membrane can be controlled with high precision using the laser spot. "This
non-invasive method is thus particularly well suited to study the effects of
receptor clustering in living cells," Tampé continues. "Our method
can be used to investigate exciting scientific questions, such as how receptors
are organized in networks and how new circuits are formed in the brain."
M. Florencia Sánchez, Sylvia Els-Heindl, Annette G. Beck-Sickinger, Ralph
Wieneke, Robert Tampé: Photo-induced receptor confinement drives
ligand-independent GPCR signaling. Science abb7657
DOI: 10.1126/science.abb7657; https://science.sciencemag.org/lookup/doi/10.1126/science.abb7657
Caption Image: Laser spots activate very small synthetic lock-and-key pairs in a matrix to create receptor clusters in the cell membrane. This ligand-independent activation triggers calcium signaling and increased cell motility. (Graphic copyright: M. Florencia Sánchez & Robert Tampé, Goethe University Frankfurt.)
Caption Movie: Upon irradiation with laser light (white rings), receptors cluster in the cell (light green circles). Thereupon, the cell moves into the direction of the receptor clusters. (Copyright: M. Florencia Sánchez & Robert Tampé, Goethe University Frankfurt). Reprinted with permission from M. F. Sánchez et al., Science 10.1126/science.abb7657(2021).
Goethe University successful in industry open call for replacement of animal components
While many studies take place in a petri glass in toxicology research, for some processes there is still a need for animal components such as serum or liver cell tissue. A team of researchers headed by Goethe University now seeks to develop a new cell culture technique to replace the use of animal components. Their project won the “CRACK IT" innovation challenge by NC3Rs, a British organisation that works to reduce reliance on animal models in research. The challenge is sponsored by AstraZeneca and Unilever.
FRANKFURT. Studies using cell cultures are necessary in toxicology research because they make it possible to test whether new substances exhibit undesirable effects. In these studies, the serum of unborn calves (Foetal Calf Serum, FCS) is often used as animal component in the cell cultures. Other “in vitro" toxicity tests also frequently use components of animal origins. The livers of laboratory rats, for example, are used to create an enzyme cocktail that helps investigate whether liver enzymes transform the substance being tested into toxic products.
Pharma producers and companies in the cosmetic industry want to find substitutes for both components, serum and liver tissue. The reasons are not only ethical nature. Tissue and serums that are taken directly from animals also introduce inaccuracies, as their composition varies depending on origin. In addition, not all components, including those of foetal calf serum, are known. That jeopardises the reproducibility of the results. In the “CRACK IT 36: Animal-free in vitro" challenge, products of animal origin are therefore to be replaced by precisely defined and reproducible alternatives.
No more animal components in cell culture nutrient solutions
Prof. Henner Hollert und Dr. Andreas Schiwy from the Department for Evolutionary Ecology and Environmental Toxicology at Goethe University and the LOEWE Centre TBG, together with the environmental toxicologist Prof. Beate Escher from the Helmholtz Centre for Environmental Research in Leipzig (UFZ) and the companies BiodetectionsSystems in Amsterdam and Scinora in Heidelberg seek to find alternatives to these animal components.
In a first step, chemically defined nutrient solutions for cell cultures will be developed – without animal components. These nutrient solutions are already common in drug manufacturing, not least for safety reasons, as they eliminate the risk that diseases such as BSE (bovine spongiform encephalopathy) are transmitted through the calf serum.
Up to now, there have been only very few such systems for toxicological testing, because the amounts required are low in comparison with pharmaceutical production. To develop them, the metabolic processes of the cells must be known in detail.
Dispensing with laboratory rats
In a second step, the researchers want to replace the enzyme cocktail from laboratory rats by having liver cell lines metabolise the substances to be tested instead. The liver cell lines are to be grown under chemically defined culture conditions. Subsequently, the metabolic products will be extracted and their effect tested in the adapted toxicological cell cultures that were developed in the first step.
Hollert and his team will first test the process on the model substance benzo[a]pyren, a substance also found in cigarette smoke. Benzo[a]pyrene is transformed into toxic substances in the human liver, which causes damage to cell DNA and impairs hormonal balance.
Funding during the first phase amounts to 100,000
pounds, or about 114,000 euros. Following a successful evaluation, the
researchers can apply in the same year for a second phase of the challenge, in
which the equivalent of about 685,000 euros over another three years may be
Prof. Henner Hollert
Head of the Department for Evolutionary Ecology and Environmental Toxicology
Institute of Ecology, Evolution and Diversity
Goethe University Frankfurt
Phone: +49 69 798-42171
Goethe University further expands scientific focus
A new research institute will be established at Goethe University: The Buber-Rosenzweig Institute will be dedicated to the study of modern and contemporary Judaism. It brings together numerous and largely third-party funded projects and contributes further to the consolidation of this research area at Goethe University. It all began with an endowed guest professorship for Jewish philosophy of religion dedicated to Martin Buber.
FRANKFURT. The new Buber-Rosenzweig Institute is intended to provide the necessary framework for increasing visibility and focusing research energies. This requires neither state funds nor funds from the department or university: Thanks to the successful acquisition of third-party funding, especially in recent times, the foundation is on a solid financial footing. "The Executive Board has unanimously approved the founding of the Institute. We are delighted about Christian Wiese's initiative. The new institute has great potential to further expand cooperation with other institutions, especially internationally, and to initiate other important projects in the future," says Prof. Enrico Schleiff, President of Goethe University.
The origins of the institute's foundation were modest but fruitful: in 1989, the Protestant Church in Hessen and Nassau established the Martin Buber Professorship as a visiting professorship at the Department of Protestant Theology. It was intended to provide students from all disciplines, especially theology and philosophy, but also interested members of the public with an insight into the past and present of Judaism and Jewish religious philosophy. In 2005, the state of Hessen permanently took over the funding, and in 2010 the endowed guest professorship was converted into a permanent professorship. Since then, Prof. Christian Wiese has taught across disciplines in theological and religious studies subjects, but also in history and philosophy. Wiese has systematically developed the professorship into an internationally visible, third-party funded and cooperating research centre. Christian Wiese is the spokesperson for the LOEWE research hub "Religious Positioning" and one of the main applicants for the interdisciplinary Graduate School "Theology as Science". He is also the international president of the Hermann Cohen Society and vice-president of the International Franz Rosenzweig Society. His most recent success was the acquisition of funding over 24 years for the academy project "Digitization of the Buber Correspondence ".
"With its numerous externally funded projects, focus on promoting young researchers and international networking, the Martin Buber Professorship is already firmly established among research institutions on modern Jewish history and culture. The status as a research institute will open up the opportunity for us to be even more visible, to focus our activities, and to attract young international scholars," says Prof. Wiese. The very fact that the institute has limited itself to a specific period of Jewish intellectual and cultural history offers great potential: under the umbrella of an institute with such a clearly defined profile will allow further projects to arise in the future. The project "Synagogue Memorial Book of Hessen" with seven to eight staff positions is currently being developed, and further research initiatives are planned. As an institute, it will also be easier to compete with other institutions. Cooperation with the Seminar for Jewish Studies and the Fritz Bauer Institute for the History and Impact of the Holocaust within Goethe University also offers great opportunities.
The institute's name refers to the two Jewish philosophers Martin Buber (1878-1965) and Franz Rosenzweig (1886-1929), who are of great importance for the history of Goethe University. Martin Buber, who was born 143 years ago, received a teaching assignment for Jewish religion and ethics in 1924, which was initially assigned to Franz Rosenzweig; later Buber became an honorary professor. Together, Buber and Rosenzweig established the Freie Jüdische Lehrhaus in Frankfurt, a Jewish educational institution for adults. Together, the two philosophers of religion undertook a translation of the Hebrew Bible into German, which Martin Buber continued after Rosenzweig's premature death in 1929 and completed in Jerusalem in 1961. In particular after 1933, the year of Hitler’s seizure of power and Buber's withdrawal from the university, the Lehrhaus became part of the Jewish resistance against National Socialist persecution.
Prof. Dr. Christian Wiese
Martin Buber Chair for Jewish Religious Philosophy
Goethe University Frankfurt
Phone: +49 69 798-33313
Goethe University research team investigates aerosal formation from iodine-containing vapours in international CLOUD project
When sea ice melts and the water surface increases, more iodine-containing vapours rise from the sea. Scientists from the international research network CLOUD have now discovered that aerosol particles form rapidly from such iodine vapours, which can serve as condensation nuclei for cloud formation. The CLOUD researchers, among them atmospheric scientists from the Goethe University Frankfurt, fear a mutual intensification of sea ice melt and cloud formation, which could accelerate the warming of the Arctic and Antarctic.
FRANKFURT. More than two thirds of the earth is covered by clouds. Depending on whether they float high or low, how large their water and ice content is, how thick they are or over which region of the Earth they form, it gets warmer or cooler underneath them. Due to human influence, there are most likely more cooling effects from clouds today than in pre-industrial times, but how clouds contribute to climate change is not yet well understood. Researchers currently believe that low clouds over the Arctic and Antarctic, for example, contribute to the warming of these regions by blocking the direct radiation of long-wave heat from the Earth's surface.
All clouds are formed by aerosols, suspended particles in the air, to which water vapour attaches. Such suspended particles or aerosols naturally consist of dusts, salt crystals or molecules released by plants. Human activities cause above all soot particles to be released into the atmosphere, but also sulphuric acid and ammonia molecules, which can cluster and form new aerosol particles in the atmosphere. Model calculations show that more than half of the cloud droplets are formed from aerosol particles that have formed in the atmosphere. For the formation of clouds, it is not decisive what the aerosol particles are made of; what matters most is their size: Aerosol particles only become condensation nuclei for cloud droplets from a diameter of about 70 nanometres and up.
In the atmosphere over the sea, aerosols released by humans play a much smaller role in the formation of low clouds than over land. Besides salt crystals originating from sea spray, aerosol particles over the sea mainly originate from certain sulphur compounds (dimethyl sufide) that are released from phytoplankton and react to form sulphuric acid, for example. At least, that is what previous research concluded.
Scientists from the CLOUD consortium have now studied the formation of aerosol particles from iodine-containing vapours. The slightly pungent smell of iodine is part of the aroma of the sea air you breathe when walking along the North Sea. Every litre of seawater contains 0.05 milligrams of iodine, and when it enters the atmosphere, iodic acid or iodous acid is formed through sunlight and ozone. The scientists simulated atmospheric conditions in mid-latitudes and arctic regions in the CLOUD experimental chamber at the CERN particle accelerator centre in Geneva, including cosmic rays simulated by an elementary particle beam.
Their findings: aerosol particle formation by iodic acid takes place very rapidly, much more rapidly than the particle formation of sulphuric acid and ammonia under comparable conditions. Ions produced by cosmic rays further promote particle formation. For the transformation of the molecular iodine into the iodine-containing acids, not even UV radiation and only a little daylight are necessary. In this way, very large aerosol quantities can be formed very quickly.
Atmospheric researcher Prof. Joachim Curtius from Goethe University explains: "Iodine aerosols can form faster than almost all other aerosol types we know. If ions produced by cosmic rays are added, each collision leads to the growth of the molecular clusters." Curtius added that this is particularly important because global iodine emissions on Earth have already tripled over the past 70 years. "A vicious circle may have been set in motion here: The pack ice thaws, which increases the water surface area and more iodine enters the atmosphere. This leads to more aerosol particles, which form clouds that further warm the poles. The mechanism we found can now become part of climate models, because iodine may play a dominant role in aerosol formation, especially in the polar regions, and this could improve climate model predictions for these regions."
The CLOUD experiment (Cosmics Leaving OUtdoor Droplets) at CERN studies how new aerosol particles are formed in the atmosphere out of precursor gases and continue to grow into condensation seeds. CLOUD thereby provides fundamental understanding of the formation of clouds and particulate matter. CLOUD is carried out by an international consortium consisting of 21 institutes. The CLOUD measurement chamber was developed with CERN know-how and is one of the cleanest experimental rooms in the world. CLOUD measurement campaigns use a variety of different measuring instruments to characterise the physical and chemical state of the particles and gases that make up the atmosphere. The team led by Joachim Curtius from the Institute for Atmosphere and Environment at Goethe University Frankfurt developes and operates two mass spectrometers in the CLOUD project to detect trace gases such as iodic acid and iodous acid even in the smallest concentrations.
Publication: Xu-Cheng He, Yee Jun Tham, Lubna Dada, Mingyi Wang, Henning Finkenzeller, Dominik Stolzenburg, Siddharth Iyer, Mario Simon, Andreas Kürten, et. al. Role of iodine oxoacids in atmospheric aerosol nucleation, Science 05 Feb 2021: Vol. 371, Issue 6529, pp. 589-595, https://doi.org/10.1126/science.abe0298
Prof. Joachim Curtius
Institute for Atmosphere and Environment
Goethe University Frankfurt am Main
Tel: +49 69 798-40258
Dr. Andreas Kürten
Institute for Atmosphere and Environment
Goethe University Frankfurt am Main
Tel: +49 (69) 798-40256
Researchers from Frankfurt and Grenoble observe disulphide bridge formation in gamma-B crystalline for the first time in the ribosomal exit tunnel
Chemical bonds within the eye-lens protein gamma-B crystallin hold the protein together and are therefore important for the function of the protein within the lens. Contrary to previous assumptions, some of these bonds, called disulphide bridges, are already formed simultaneously with the synthesis of the protein in the cell. This is what scientists at Goethe University Frankfurt, Max Planck Institute of Biophysics and the French Institute de Biologie Structurale in Grenoble have discovered.
FRANKFURT. The lens of the human eye gets its transparency and refractive power from the fact that certain proteins are densely packed in its cells. These are mainly crystallines. If this dense packing cannot be maintained, for example due to hereditary changes in the crystallines, the result is lens opacities, known as cataracts, which are the most common cause of vision loss worldwide.
In order for crystallins to be packed tightly in lens fibre cells, they must be folded stably and correctly. Protein folding already begins during the biosynthesis of proteins in the ribosomes, which are large protein complexes. Ribosomes help translate the genetic code into a sequence of amino acids. In the process, ribosomes form a protective tunnel around the new amino acid chain, which takes on three-dimensional structures with different elements such as helices or folded structures immediately after the tunnel's formation. The gamma-B crystallines studied in Frankfurt and Grenoble also exhibit many bonds between two sulphur-containing amino acids, so-called disulphide bridges.
The production of these disulphide bridges is not easy for the cell, since biochemical conditions prevail in the cell environment that prevent or dissolve such disulphide bridges. In the finished gamma-B crystalline protein, the disulphide bridges are therefore shielded from the outside by other parts of the protein. However, as long as the protein is in the process of formation, this is not yet possible.
But because the ribosomal tunnel was considered too narrow, it was assumed - also on the basis of other studies - that the disulphide bridges of the gamma-B crystallins are formed only after the proteins have been completed. To test this assumption, the researchers from Frankfurt and Grenoble used genetically modified bacterial cells as a model system, stopped the synthesis of the gamma-B crystallins at different points in time and examined the intermediate products with mass spectrometric, nuclear magnetic resonance spectroscopic and electron microscopic methods, and supplemented these with theoretical simulation calculations. The result: The disulphide bridges are already formed on the not yet finished protein during the synthesis of the amino acid chain.
"We were thus able to show that disulphide bridges can already form in the ribosomal tunnel, which offers sufficient space for this and shields the disulphide bridges from the cellular milieu," says Prof. Harald Schwalbe from the Institute of Organic Chemistry and Chemical Biology at Goethe University. "Surprisingly, however, these are not the same disulphide bridges that are later present in the finished gamma-B crystallin. We conclude that at least some of the disulphide bridges are later dissolved again and linked differently. The reason for this probably lies in the optimal timing of protein production: the 'preliminary' disulphide bridges accelerate the formation of the 'final' disulphide bridges when the gamma-B crystallin is released from the ribosome."
In further studies, the researchers now want to test whether the synthesis processes in the slightly different ribosomes of higher cells are similar to those in the bacterial model system.
Publication: Linda Schulte, Jiafei Mao, Julian Reitz, Sridhar Sreeramulu, Denis Kudlinzki,
Victor-Valentin Hodirnau, Jakob Meier-Credo, Krishna Saxena, Florian Buhr, Julian D. Langer, Martin Blackledge, Achilleas S. Frangakis, Clemens Glaubitz, Harald Schwalbe: Cysteine oxidation and disulfide formation in the ribosomal exit tunnel. Nature Communications https://doi.org/10.1038/s41467-020-19372-x
Prof. Dr. Harald Schwalbe
Institute for Chemistry and Chemical Biology
Center for Biomolecular Magnetic Resonance (BMRZ)
Goethe University Frankfurt
Tel +49 69 798-29137