Publication in "Nature": Decision-making in immune response solved
FRANKFURT. Social media have become an indispensable part of our everyday life. We use them constantly to screen the latest news and share pre-selected information. The cells in our body do a similar thing. Information is pre-selected and transmitted to the immune system in order to fight against unwelcome invaders, such as viruses, bacteria, parasites or cancer. This pre-selection occurs by means of a highly complex molecular machine. Biochemists at Goethe University Frankfurt and the Max Planck Institute of Biophysics, in cooperation with researchers at Martin Luther University Halle-Wittenberg, have now unveiled the inner workings of this complex molecular machine.
Status updates of each cell are transmitted from the cell’s interior to the immune system in the form of small protein fragments. These fragments are presented on the cell surface by specific proteins, known as MHC-I molecules. Cancerous or infected cells can thus be quickly identified and eliminated. However, viruses and tumours can also trick the immune system and in so doing escape immune surveillance. In addition, ambiguous messages can lead to autoimmune diseases or chronic inflammation.
That is why it is particularly important to understand how this highly complex molecular machine in the cell’s interior selects the relevant protein fragments and coordinates the loading of MHC-I molecules. In the current issue of the renowned scientific journal NATURE, the researchers from Frankfurt and Halle provide first insights into the molecular architecture and inner workings of what is referred to as the MHC-I peptide-loading complex.
“We had to pull out all the stops to prepare this extremely fragile complex for structural analyses,” explains Dr. Simon Trowitzsch of the Institute of Biochemistry at Goethe University Frankfurt. “First of all, we expanded our biochemical toolbox and developed a viral molecular bait that allowed us to isolate the native MHC-I peptide-loading complex from the endoplasmic reticulum.”
“Thanks to groundbreaking advances in cryo-electron microscopy, which were recently awarded the Nobel Prize, we were able to look closely at the MHC-I peptide-loading complex - which is about a hundred thousand times smaller than a pinhead - and to determine its molecular structure,” reports Dr. Arne Möller from the Max Planck Institute of Biophysics.
The scientists can now deduce how the cell manages to generate information important for the immune system. Its structure shows how transport proteins in the membrane, folding enzymes and MHC-I molecules are working together precisely within a highly dynamic complex.
“Our research shows how the MHC-I peptide-loading complex filters out only those fragments of information which are actually needed by the immune system’s effector cells. These findings have solved a decades-old puzzle and allow us now to describe the antigen selection process with greater precision. This knowledge will help to further improve immunotherapies,” concludes Professor Robert Tampé from the Institute of Biochemistry.
Publication: Andreas Blees, Dovilė Janulienė, Tommy Hofmann, Nicole Koller, Carla Schmidt, Simon Trowitzsch, Arne Moeller & Robert Tampé: Structure of the human MHC-I peptide-loading complex, NATURE (Nov 6, 2017, First Release) doi:10.1038/nature24627
A picture can be downloaded from: www.uni-frankfurt.de/69093715
Caption: Structure of the MHC-I peptide-loading complex in the membrane of the endoplasmic reticulum.
Image rights: Arne Möller (Max Planck Institute of Biophysics), Simon Trowitzsch and Robert Tampé (Goethe University Frankfurt)
Further information: Professor Dr. Robert Tampé and Dr. Simon Trowitzsch, Institute of Biochemistry, Faculty of Biochemistry, Chemistry and Pharmacy, Riedberg Campus, Tel.: +49(0)69-798-29475, Tel.: +49(0)69-798-29273, firstname.lastname@example.org, Trowitzsch@biochem.uni-frankfurt.de; Dr. Arne Möller, Max Planck Institute of Biophysics, Tel.: +49(0)69-6303-3057, email@example.com.
Archaeologists from Goethe University return from a successful expedition
FRANKFURT. A team of Frankfurt-based archaeologists has returned from the Iraqi-Kurdish province of Sulaymaniyah with new findings. The discovery of a loom from the 5th to 6th century AD in particular caused a stir.
The group of Near Eastern archaeology undergraduates and doctoral students headed by Prof. Dirk Wicke of the Institute of Archaeology at Goethe University were in Northern Iraq for a total of six weeks. It was the second excavation campaign undertaken by the Frankfurt archaeologist to the approximately three-hectare site of Gird-î Qalrakh on the Shahrizor plain, where ruins from the Sasanian and Neo-Assyrian period had previously been uncovered. The region is still largely unexplored and has only gradually opened up for archaeological research since the fall of Saddam Hussein.
The objective of the excavations on the top and slope sections of the settlement hill, some 26 meters high, was to provide as complete a sequence as possible for the region's ceramic history. Understanding the progression in ceramics has long been a goal of research undertaken on the Shahrizor plain, a border plain of Mesopotamia with links to the ancient cultural regions of both Southern Iraq and Western Iran. These new insights will make it easier to categorise other archaeological finds chronologically. The excavation site is ideal for establishing the progression of ceramics, according to archaeology professor Dirk Wicke: "It is a small site but it features a relatively tall hill in which we have found a complete sequence of ceramic shards. It seems likely that the hill was continuously inhabited from the early 3rd millennium BC through to the Islamic period."
However, the archaeologists had not expected to find a Sasanian loom (ca. 4th-6th century AD), whose burnt remnants, and clay loom weights in particular, were found and documented in-situ. In addition to the charred remains, there were numerous seals, probably from rolls of fabric, which indicate that large-scale textile production took place at the site. From the neo-Assyrian period (ca. 9th-7th century BC), by contrast, a solid, stone-built, terraced wall was discovered, which points to major construction work having taken place at the site. It is possible that the ancient settlement was refortified and continued to be used in the early 1st millennium BC.
Work on the project was initiated by Prof. Wicke in 2015 with support from the local Antiquities Service as well as the Enki e.V. association situated at Goethe University and the Thyssen Foundation. Work is set to continue next year depending on further funding and the political development in the Iraqi-Kurdish region.
Images to download can be found under the following link: http://www.uni-frankfurt.de/68944552
Image 1: Aerial view of the site from the south showing the excavation areas on the summit and south-western slope as well as the small test pit on the south-eastern slope. Photo: Philipp Serba
Image 2: Neo-Assyrian cylinder seal and imprint on right, height 3.9 cm. It depicts two winged genies on a sacred tree. Photo: Dr. Jutta Eichholz
Image 3: Excavated corner of room with remnants of the loom between the wall (top) and a bench of six mudbricks. The round loom weights made from clay are particularly visible, as are slabs of mud once forming some kind of shelving. Photo: Lanah Haddad
Information: Prof. Dr. Dirk Wicke, Institute of Archaeologicaly, Near Eastern Archaeology, Norbert-Wollheim-Platz 1, 60629 Frankfurt am Main, Germany, Telephone +49 (0)69 798 32317, Secretary's Office +49 (0)69 798 32313
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 firstname.lastname@example.org, 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)