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New microscopy method makes dimerization of membrane receptors visible
FRANKFURT. The surface of every cell contains receptors that react to external signals similar to a “gate”. In this way, the cells of the innate immune system can differentiate between friend and foe partly through their “toll-like receptors” (TLRs). Two parts of this gate often work together here, as researchers at Goethe University Frankfurt and their British colleagues have now found out with the help of a new super-resolution optical microscopy technique.
When the German Nobel Prize winner Christiane Nüsslein-Volhard discovered receptors in the fruit fly (Drosophila melanogaster) in the 1990s that transduced signals from the cell surface into a cellular response, she was amazed. She nicknamed the receptors “toll” (amazing) and this term has meanwhile become firmly established in scientific literature. Since then, similar receptors (toll-like receptors) have also been discovered in animals and humans. They recognize bacteria, viruses and fungi and thus ensure that our body reacts to infections in a suitable way. By contrast, de-regulated TLRs can lead to chronic inflammatory conditions and cancer.
Experiments conducted so far indicated that TLRs are activated by a chemical signal that causes two proteins to cluster together as dimers. This process, which is known as “dimerization”, appears to play a pivotal role in a cell’s fate: It can decide whether the cell survives, dies or moves within the body. Because dimerization takes place on a molecular scale that cannot be captured using conventional microscopy techniques, researchers have to date been dependent on indirect measuring methods. These were, however, prone to error and yielded diverging results. This has now changed thanks to the new super-resolution optical microscopy technique.
In the forthcoming issue of “Science Signaling”, the working groups led by Professor Mike Heilemann of Goethe University Frankfurt and by Dr. Darius Widera and Dr. Graeme Cottrell of the University of Reading in England describe how they have studied the organization of the TLR4 receptor on the cell surface in molecular resolution. In a first step, they used a super-resolution microscope with a resolution about 100 times better than a standard fluorescence microscope. Since this was still not sufficient to make single receptor molecules in a tiny protein dimer visible, the researchers developed a more sophisticated analysis of the optical signal. In this way they were able to zoom in closer on the super-resolution images and examine under which conditions TLR4 forms a monomer or a dimer. The researchers could also detect which chemical signals from different pathogens modulate the receptors’ patterns.
The researchers hope that their work will lead in future to a better understanding of how TLR dimerization affects the decision between the life or death of a cell. It might also be possible to determine how pharmaceutical ingredients targeted at TLRs influence the behavior of cancer cells. “It is also conceivable that this approach will help us in future to understand better the fundamental biological processes that regulate the immune system in health and disease. At the same time, this microscopy method is also applicable to other membrane proteins and many similar questions,” explains Professor Mike Heilemann from the Institute of Physical and Theoretical Chemistry at Goethe University Frankfurt.
Carmen L. Krüger, Marie-Theres Zeuner, Graeme S. Cottrell, Darius Widera, Mike Heilemann: Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization, Science Signaling, doi: 10.1126/scisignal.aan1308
A picture can be downloaded under http://www.muk.uni-frankfurt.de/68944753
Left: Conventional light microscopy is an useful tool in visualising biological structures and processes. However, its resolution is not sufficient to study events occurring at molecular scale. The image on the left shows the nuclei of brain tumour cells (yellow: nuclei containing DNA) with Toll-like receptors 4 localised at the cell surface (cyan spots). Although many TLR4 can be clearly seen, the spatial resolution does not allow determination of single receptor units. Middle: Super-resolution microscopy greatly improves the spatial resolution and allows detection of single TLR4 clusters (cyan) at the surface of the cells. However, even at this superior resolution, it is not possible to distinguish between monomers and dimers of the receptor. Right: Crystal structure of a TLR4 dimer. The novel analysis method developed by the consortium is able to provide information allowing differentiating between receptor monomers and dimers.
Further information: Professor Mike Heilemann, Institute of Physical and Theoretical Chemistry, Faculty of Biochemistry, Chemistry and Pharmacy, Riedberg Campus, Tel.: +49(0)69-798- 29736, Heilemann@chemie.uni-frankfurt.de.
Science publication describes quality control of antigens
FRANKFURT. The immune system monitors the health status of the cells in our bodies by examining a kind of molecular passport. Sometimes cells present the wrong passport, which can lead to autoimmune diseases, chronic inflammation, or cancer. In the new issue of the journal "Science" (first release), scientists of the Goethe University Frankfurt have now elucidated the mechanism of how the correct molecular passport is selected.
Most cells provide the T cells of the adaptive immune system with information about their condition by presenting selected components of their interior (antigens) on their surface. If these components include fragments of viruses or altered cell components, the affected cell is eliminated by the T cells. The selection of the antigens is crucial in this process. Presenting the wrong antigens leads to either healthy cells being attacked by the immune system - causing autoimmune diseases or chronic inflammation - or to diseased cells not being recognized, allowing cancer cells or virus-infected cells to escape immune surveillance.
Dr. Christoph Thomas and Prof. Robert Tampé from the Institute of Biochemistry at Goethe University have now unraveled on a molecular level how antigens are selected in the cell for presentation on the cell surface. The protein structure they present shows for the first time the kind of quality control antigens undergo to enable a precise and effective immune response.
"Our work solves a 30-year-old problem of cellular immunity, in particular how antigens associated with tumors or pathogens are selected through processes of editing and quality control in order to generate a specific immune response", explains Prof. Robert Tampé the significance of the publication.
Christoph Thomas, Robert Tampé: Structure of the TAPBPR–MHC I complex defines the mechanism of peptide loading and editing, Science (Oct 12, 2017, First Release)
An image for download can be found here:
Image captation: Space-filling model of the solved protein complex responsible for antigen selection.
Goethe University’s Museum Giersch shows pictures of a nearly forgotten artist couple
The visual artist Eric Isenburger (1902–1994) and his wife and muse, expressionist dancer Jula Isenburger, née Elenbogen (1908–2000), are among the 20th century’s almost completely forgotten artist personalities. Now, for the first time, the Museum Giersch der Goethe-Universität is dedicating a comprehensive retrospective exhibition in Eric’s native city.
Eric Isenburger’s training at Frankfurt’s Kunstgewerbeschule was followed by numerous study trips and a longer stay in Barcelona. Together with his wife, he initially lived in Vienna and subsequently in Berlin as an independent artist and stage designer. As Jews, the couple were subject to repressive measures by the National Socialist dictatorship as early as 1933, and began the Odyssey of their flight: Paris, Stockholm, Southern France and the French internment camps Les Milles and Camp de Gurs were stations in the years that followed, until in 1941 they finally obtained a visa for the USA and were able to leave Europe via Lisbon to New York, where they lived for the rest of their lives.
Despite these conditions, some of which were extremely difficult, Eric Isenburger created an original artistic oeuvre comprising portraits, landscapes and still lifes. With a late-Impressionist stamp, in part expressive style and in terms of material technique an experimental posture, Isenburger the painter took the outer world as his point of departure, but refrained from all-too obvious commentary on his times. His extraordinary oeuvre is truly a discovery.
“Von Frankfurt nach New York” (“From Frankfurt to New York): Eric und Jula Isenburger, 15. Oktober 2017 bis 11. Februar 2018, Museum Giersch der Goethe-Universität, Schaumainkai 83, 60596 Frankfurt am Main, Telefon +49 (0) 69 13 82 101-0, E-Mail email@example.com, www.museum-giersch.de
Private guided tours (on request) Tuesday through Friday 60 Euro, Saturday and Sunday 65 Euro (in addition to the entrance fee)
Research unit validates upgraded models in second funding period
FRANKFURT. Gravity waves form in the atmosphere as a result of destabilizing processes, for example at weather fronts, during storms or when air masses stroke over mountain ranges. They can occasionally be seen in the sky as bands of cloud. For weather forecast and climate models, however, they are mostly “invisible” due to their short wavelength. The effects of gravity waves can only be taken into consideration by including additional special components in the models. The “MS-GWaves” research unit funded by the German Research Foundation and led by Goethe University Frankfurt has meanwhile further developed such parameterizations and will test them in the second funding period.
Although gravity waves have comparatively short wavelengths of between just a few hundred metres and several hundred kilometres, at times they influence the transport of water vapour as well as large-scale winds and temperature distributions to a considerable degree. This effect is strongest in the upper layers of the atmosphere. These, in turn, have such a strong effect on the lower layers too that a realistic modelling of weather and climate in the atmosphere is impossible without giving due consideration to gravity waves. Gravity waves also play a significant role for air traffic in predicting turbulence and are an important factor in weather extremes, such as heavy rain or storms.
In the first funding period, the ten research institutes participating in the project documented in detail the formation of gravity waves in one of the largest measuring campaigns ever undertaken, using radar, high-performance lasers, rockets and research planes as well as through laboratory tests. They also refined the hypothesis on the formation and dispersion of gravity waves to such an extent that their development can now be reproduced much more reliably in high-resolution numerical models too.
In a further step, the research unit led by Professor Ulrich Achatz of the Department of Atmospheric and Environmental Sciences at Goethe University Frankfurt has used these findings to improve parameterizations, which serve to describe the influence of gravity waves, in weather and climate models with typically coarser resolution. They have refined the weather and climate model ICON used by Germany's National Meteorological Service (DWD) and the Max Planck Institute for Meteorology. The new model, UA-ICON, allows more precise predictions for the upper atmosphere and can be operated with different resolutions, so that gravity waves can either be simulated in it for test purposes or must be parameterized in the operational mode. The advanced parameterizations are now being integrated in this model and tested in the second funding period.
The project will also focus on impacts on weather prediction and climate modelling. An important aspect in this context is a better description of the interaction between gravity waves and ice clouds (cirrus), undertaken in cooperation with the University of Mainz. It could well be that this plays an important role for the climate.
Further information: Professor Ulrich Achatz, Department of Atmospheric and Environmental Sciences, Faculty of Geosciences and Geography, Riedberg Campus, Tel.: +49(0)69-798-40243, firstname.lastname@example.org.
Konstantinos Stellos awarded ERC Starting Grant
FRANKFURTAtherosclerosis, the most frequent cause of death in the western world, usually starts with an inflammation of arterial endothelial cells, a process that affects the structure and function of blood vessels and may ultimately lead to an acute heart attack or stroke. It is still unclear so far how endothelial cells “sense” the environmental stimuli and how pro-inflammatory processes are controlled. With the help of an ERC Starting Grant of € 1.5 million awarded by the European Research Council, Professor Konstantinos Stellos of Goethe University Frankfurt now plans to examine the process at single nucleotide-level of RNA molecules.
Increasing recent evidence suggests that RNA is not just a passive copy of the genetic code necessary for the production of proteins, the building blocks of cells, but also important for regulating intracellular transport and stability of genetic information, thus allowing or inhibiting its decoding to proteins. Even today, how RNA reacts to its ambient surroundings is not fully understood. For example, it is still far from clear whether chemical modifications to the RNA have an influence on gene expression, endothelial cell function and therefore on atherosclerosis.
The research group led by Konstantinos Stellos from the Institute of Cardiovascular Regeneration and the Department of Cardiology at Goethe University Frankfurt has observed two particularly common chemical modifications in the RNA of endothelial cells that occur in atherosclerosis. His intention now is to investigate another RNA modification in detail, namely the impact of RNA methylation on blood vessel function.
The researchers aim to increase our understanding of how RNA methylation affects gene expression, which proteins play a role in this context and what impact RNA methylation has on vascular inflammation and atherosclerosis. Their findings will be further “translated” into patients with coronary heart disease. They also hope to detect biomarkers which reveal early signs of atherosclerosis in the general population as well as develop new therapeutic strategies for this common disease.
Konstantinos Stellos completed his medical degree in Greece in 2005 and two years later his doctorate at the University of Tübingen. His “habilitation” (postdoctoral lecture qualification) followed in 2013 at Goethe University Frankfurt. Since 2013, he is board-certified cardiologist and group leader at the Institute of Cardiovascular Regeneration of Goethe University Frankfurt.
With the ERC Starting Grant, the European Union funds excellent early-career scientists after their doctorate so they can launch an independent career and establish their own research team.
Further information: https://erc.europa.eu/news/erc-2017-starting-grants-results or www.stelloslab.com