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Antigen binding does not trigger any structural changes in T-cell receptors – Signal transduction probably occurs after receptor enrichment
T cells are our immune system's customised tools for fighting infectious diseases and tumour cells. On their surface, these special white blood cells carry a receptor that recognises antigens. With the help of cryo-electron microscopy, biochemists and structural biologists from Goethe University Frankfurt, in collaboration the University of Oxford and the Max Planck Institute of Biophysics, were able to visualise the whole T-cell receptor complex with bound antigen at atomic resolution for the first time. Thereby they helped to understand a fundamental process which may pave the way for novel therapeutic approaches targeting severe diseases.
FRANKFURT. The immune system of vertebrates is a powerful weapon against external pathogens and cancerous cells. T cells play a curcial role in this context. They carry a special receptor called the T-cell receptor on their surface that recognises antigens – small protein fragments of bacteria, viruses and infected or cancerous body cells – which are presented by specialised immune complexes. The T-cell receptor is thus largely responsible for distinguishing between “self" and “foreign". After binding of a suitable antigen to the receptor, a signalling pathway is triggered inside the T cell that “arms" the cell for the respective task. However, how this signalling pathway is activated has remained a mystery until now – despite the fact that the T-cell receptor is one of the most extensively studied receptor protein complexes.
Many surface receptors relay signals into the interior of the cell by changing their spatial structure after ligand binding. This mechanism was so far assumed to also pertain to the T-cell receptor. Researchers led by Lukas Sušac, Christoph Thomas, and Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt, in collaboration with Simon Davis from the University of Oxford and Gerhard Hummer from the Max Planck Institute of Biophysics, have now succeeded for the first time in visualizing the structure of a membrane-bound T-cell receptor complex with bound antigen. A comparison of the antigen-bound structure captured using cryo-electron microscopy with that of a receptor without antigen provides the first clues to the activation mechanism.
For the structural analysis, the researchers chose a T-cell receptor used in immunotherapy to treat melanoma and which had been optimised for this purpose in several steps in such a way that it binds its antigen as tightly as possible. A particular challenge on the way to structure determination was to isolate the whole antigen receptor assembly consisting of eleven different subunits from the cell membrane. “Until recently, nobody believed that it would be possible at all to extract such a large membrane protein complex in a stable form from the membrane," says Tampé.
Once they had successfully achieved this, the researchers used a trick to fish those receptors out of the preparation that had survived the process and were still functional: due to the strong interaction between the receptor complex and the antigen, they were able to “fish" one of the most medically important immune receptor complexes. The subsequent images collected at the cryo-electron microscope delivered groundbreaking insights into how the T-cell receptor works, as Tampé summarises: “On the basis of our structural analysis, we were able to show how the T-cell receptor assembles and recognises antigens and hypothesise how signal transduction is triggered after antigen binding." According to their results, the big surprise is that there is evidently no significant change in the receptor's spatial structure after antigen binding, as this was practically the same both with and without an antigen.
The remaining question is how antigen
binding could instead lead to T-cell activation. The co-receptor CD8 is known
to approach the T-cell receptor after antigen binding and to stimulate the
transfer of phosphate groups to its intracellular part. The researchers assume
that this leads to the formation of structures which exclude enzymes that
cleave off phosphate groups (phosphatases). If these phosphatases are missing,
the phosphate groups remain stable at the T-cell receptor and can trigger the
next step of the signalling cascade. “Our structure is a blueprint for future
studies on T-cell activation," Tampé is convinced. “In addition, it's an important
stimulus for employing the T-cell receptor in a therapeutic context for treating
infections, cancer, and autoimmune diseases."
Publication: Lukas Sušac, Mai T. Vuong, Christoph Thomas, Sören von Bülow, Caitlin O'Brien-Ball, Ana Mafalda Santos, Ricardo A. Fernandes, Gerhard Hummer, Robert Tampé, Simon J. Davis: Structure of a fully assembled tumor-specific T-cell receptor ligated by pMHC. Cell (2022) 185, Aug 18 https://doi.org/10.1016/j.cell.2022.07.010
Picture download: https://www.uni-frankfurt.de/123390758
Caption: The cryo-EM structure of the fully assembled T-cell receptor (TCR) complex with a tumor-associated peptide/MHC ligand provides important insights into the biology of TCR signaling. These insights into the nature of TCR assembly and the unusual cell membrane architecture reveal the basis of antigen recognition and receptor signaling.
Professor Robert Tampé
Collaborative Research Centre CRC 1507 – Protein Assemblies and Machineries in Cell Membranes
Institute of Biochemistry, Biocenter
Goethe University Frankfurt
Tel.: +49 69 798-29475
New international study generates insights into the inner workings of the adaptive immune response
How do killer T cells recognise cells in the body that have been infected by viruses? Matter foreign to the body is presented on the surface of these cells as antigens that act as a kind of road sign. A network of accessory proteins – the chaperones – ensure that this sign retains its stability over time. Researchers at Goethe University have now reached a comprehensive understanding of this essential cellular quality control process. Their account of the structural and mechanistic basis of chaperone networks has just appeared in the prestigious science journal Nature Communications. These new findings could be harbingers of progress in areas such as vaccine development.
FRANKFURT. Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.
At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is “processed" or assembled in the cell – in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells – we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.
The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. “With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: “The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.
As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: “Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.
In what directions does the study point? “We now better understand
which peptides are loaded and how this occurs now. We can also more reliably
predict the dominant peptide epitopes, in other words the stable peptide
epitopes that will be selected by the chaperone network." Tampé hopes that the
new findings will prove useful for developing future vaccines against virus variants.
They could also facilitate progress on future tumour therapies. “Both topics
are directly linked. But the applications in tumour therapy are certainly more
complex and more for the long term."
Publication: Alexander Domnick, Christian Winter, Lukas Sušac, Leon Hennecke, Mario Hensen, Nicole Zitzmann, Simon Trowitzsch, Christoph Thomas, Robert Tampé: “Molecular basis of MHC I quality control in the peptide loading complex" Nature Communications 2022, 13:4701 https://doi.org/10.1038/s41467-022-32384-z
An image to download (copyrights Christoph Thomas & Robert Tampé): https://www.uni-frankfurt.de/123213123
Caption: The mechanism of MHC I assembly, epitope editing and quality control within the peptide loading complex (PLC). The fully assembled PLC machinery of antigen processing is formed by the antigen transport complex TAP1/2, the chaperones calreticulin, ERp57, and tapasin, and the heterodimeric MHC I (heavy and light chain in teal and green, respectively).
Institute of Biochemistry
Goethe University Frankfurt
Prof. Dr Robert Tampé
Tel: +49 (0)69 79829475
A feedback loop sensitises the auditory cortex to acoustic reflections
Neuroscientists at Goethe University, Frankfurt have
discovered a feedback loop that modulates the receptivity of the auditory
cortex to incoming acoustic signals when bats emit echolocation calls. In a
study published in the journal “Nature Communications", the researchers show that
information transfer in the neural circuits involved switched direction in the
course of call production. It seems likely that this feedback prepares the
auditory cortex for the expected echoes of the emitted calls. The researchers
interpret their findings as indicating that the importance of feedback loops in
the brain is currently still underestimated.
FRANKFURT. Bats famously have an ultrasonic navigation system: they use their extremely sensitive hearing to orient themselves by emitting ultrasonic sounds and using the echoes that result to build up a picture of their environment. For example, Seba's short-tailed bat (Carollia perspicillata) finds the fruits that are its preferred food using this echolocation system. At the same time, bats also use their vocalisations to communicate with other bats. They use a somewhat lower range of frequencies for this purpose.
Neuroscientist Julio C. Hechavarría from the Institute of Cell Biology and Neuroscience at Goethe University and his team are investigating the brain activities associated with vocalisations in Seba's short-tailed bat. Their most recent study investigates how the auditory cortex and the frontal lobe work together in echolocation. The auditory cortex processes auditory information and the frontal lobe is a region in the forebrain that is associated, in humans, with tasks that include planning actions. To discover more about this, the researchers inserted tiny electrodes into the bats' brains to record neural activity in the frontal lobe and the auditory cortex.
The researchers succeeded in identifying a feedback loop that had previously been entirely unknown in the frontal lobe-auditory cortex network of bats emitting echolocation calls. Information normally flows from the frontal lobe, where call production is planned, to the auditory cortex to ready it to expect an acoustic signal. But it was observed that the flow of information from the frontal lobe to the auditory cortex diminished after the emission of an echolocation pulse until the direction of information transfer switched completely and information flowed from the auditory cortex back to the frontal lobe. Hechavarría hypothesises that this feedback loop readies the auditory cortex to better receive the sounds reflected back from the echolocation call.
The neurobiologists simulated signals originating from the auditory cortex by electrically stimulating the frontal lobe. The activity this generated in the frontal lobe had the expected effect of prompting the auditory cortex to respond more strongly to acoustic reflections. “This shows that the feedback loop we found is functional", neurobiologist Hechavarría sums up. He takes up the metaphor of a highway to illustrate the significance of these findings: “Up to now, it was generally believed that the flow of data on this information superhighway mainly runs in one direction and that feedback loops are exceptions. Our data show that this view is most likely incorrect and that feedback loops in the brain are probably considerably more significant than has previously been hypothesised."
no pronounced reversal of information flow was observed for bat vocalisations
used for communication purposes. “This may be because the bats were alone in a
sound-proofed and electrically isolated chamber and therefore did not expect a
response to their calls", Hechavarría speculates before going on to note: “One
of the aspects that makes our study so interesting is that it opens up new ways
to study the social interactions of bats. We want to continue work in this area
in the future."
Publication: Francisco García-Rosales, Luciana López-Jury, Eugenia Gonzalez-Palomares, Johannes Wetekam, Yuranny Cabral-Calderín, Ava Kiai, Manfred Kössl, Julio C. Hechavarría: Echolocation-related reversal of information flow in a cortical vocalisation network. Nature Communications 13, 3642 (2022) https://doi.org/10.1038/s41467-022-31230-6
An image to download: https://www.uni-frankfurt.de/122772504
Caption: Bats “see" with their ears. Researchers at Goethe University have discovered how the auditory cortex is readied for incoming acoustic signals. (Photo: Dr. Julio C. Hechavarría)
Dr. Julio C. Hechavarría (Ph.D.)
Auditory Computations Group (Group Leader)
Institute for Cell Biology and Neuroscience
Tel. +49 (0)69 798-42050
A research team with members from Goethe University Frankfurt and the University of Michigan in the USA is using bacterial biosynthesis to produce an antibiotic containing fluorine –The technology is being commercialized by a startup
The use of the element fluorine to modify active substances is an important tool in modern drug development. A team at Goethe University Frankfurt has now achieved an important “first" by successfully fluorinating a natural antibiotic via targeted bioengineering. With this method, an entire substance class of medically relevant natural products can be modified. The method has enormous potential for the manufacture of new antibiotics against resistant bacterial pathogens and for the (further) development of other drugs. The startup kez.biosolutions GmbH will bring these research results to the application stage (Nature Chemistry, DOI 10.1038/s41557-022-00996-z).
FRANKFURT/MAIN. Active drug agents have been chemically modified with fluorine for decades, owing to its numerous therapeutic effects: Fluorine can strengthen the bonding of the active agent to the target molecule, make it more accessible to the body, and altering the time it spends in the body. Nearly half of the small-molecule drugs (molecules up to approx. 100 atoms) currently approved by the U.S. Food and Drug Administration (FDA) contain at least one chemically bound fluorine atom. These include such different drugs as cholesterol-lowering agents, antidepressants, anticancer agents and antibiotics.
Bacteria and fungi often manufacture complex natural compounds to obtain a growth advantage. One possible route for the development of drugs from natural compounds is to modify these substances by adding one or more fluorine atoms. In the case of the antibiotic erythromycin, for example, the attached fluorine atom confers important advantages. The new erythromycin manufactured via this process can be accessed more easily by the body and is more effective against pathogenic microorganisms that have developed resistance to this antibiotic. However, the synthetic-chemical methods for inserting fluorine into natural substances are very complicated. Owing to the chemical and reaction conditions that are necessary, these methods are frequently "brutal," says Martin Grininger, Professor for Organic Chemistry and Chemical Biology at Goethe University. "This means, for example, that we are very limited in selecting the positions where the fluorine atom can be attached," he adds.
A German-U.S. scientific team headed by Prof. Martin Grininger and Prof. David Sherman, Professor of Chemistry at the University of Michigan, has now succeeded in utilizing the biosynthesis of an antibiotic-producing bacteria. In this process, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of a macrolide antibiotic. “We introduce the fluorinated unit during the natural manufacturing process, an approach that is both effective and elegant," stresses Grininger, "This gives us great flexibility when positioning the fluorine in the natural substance – and allows us to influence its efficacy."
To this end the project leaders Dr. Alexander Rittner and Dr. Mirko Joppe – both members of Grininger's research group in Frankfurt – inserted a subunit of an enzyme called fatty acid synthase into the bacterial protein. The enzyme is naturally involved in the biosynthesis of fats and fatty acids in mice. The fatty acid synthase is not very selective in processing the precursors, which are also important for the manufacture of antibiotics in bacteria, Rittner explains. With an intelligent product design, the team succeeded in integrating a subunit of the murine enzyme into the corresponding biosynthetic process for the antibiotic. "The exciting part is that, with erythromycin, we were able to fluorinate a representative of a gigantic substance class, the so-called polyketides," says Rittner. “There are about 10,000 known polyketides, many of which are used as natural medicines –for example, as antibiotics, immunosuppressives or cancer drugs. Our new method thus possesses a huge potential for the chemical optimization of this group of natural substances – in the antibiotics primarily to overcome antibiotic resistance." To exploit this potential, Dr. Alexander Rittner founded the startup kez.biosolutions GmbH.
Prof. Martin Grininger has been conducting research on the tailor-made biosynthesis of polyketides for several years. "Our success in fluorinating macrolide antibiotics is a breakthrough we worked hard to achieve and of which I am now very proud" he says. “This success is also an impetus for the future. We are already testing the antibiotic effect of various fluorinated erythromycin compounds and additional fluorinated polyketides. We intend to expand this new technology to include additional fluorine motifs in collaboration with Prof. David Sherman and his team at the University of Michigan in the U.S."
The search for drugs that overcome antibiotic resistance is a long-term task: depending on how frequently they are used, all antibiotics naturally cause resistances sooner or later. Against this background Dr. Mirko Joppe also believes that his work has broader implications for society. "Research on antibiotics is not economically lucrative for various reasons. It is therefore the task of the universities to close this gap by developing new antibiotics in cooperation with pharmaceutical companies," he explains. "Our technology can be used to generate new antibiotics simply and quickly and now offers ideal contact points for projects with industrial partners."
The research work on polyketides described
above was supported by the Volkswagen Foundation (within the framework of a Lichtenberg
Professorship), the LOEWE MegaSyn research initiative funded by the Hessian
Ministry for Science and the Arts, and the National Institute of Health in the U.S.
Publication: Alexander Rittner, Mirko Joppe, Jennifer J. Schmidt, Lara Maria Mayer, Simon Reiners, Elia Heid, Dietmar Herzberg, David H. Sherman, Martin Grininger: Chemoenzymatic synthesis of fluorinated polyketides. Nature Chemistry (2022) https://www.nature.com/articles/s41557-022-00996-z
Image to download: https://www.uni-frankfurt.de/122764926
Caption: Scientists working at Goethe University Frankfurt have created an enzyme capable of producing fluorinated antibiotics via a series of reactions. For clarity, the different regions of the hybrid that interact in this context are shown in different colors. (Graphic: Grininger)
Prof. Dr. Martin Grininger
Institute for Organic Chemistry and Chemical Biology
Buchmann Institute for Molecular Life Sciences
Goethe University Frankfurt
Tel.: +49 (0)69 798-42705
A study among students from 41 countries provides orientation for university education
Environmental students from countries with lower prosperity indicators rate the 17 Sustainable Development Goals of the United Nations as more important than environmental students from countries with higher prosperity indicators do. Moreover, they mostly assign the goals to only one pillar of sustainability, either social, economic or environmental sustainability. This is the conclusion drawn by a study by Goethe University Frankfurt, which is based on an online survey in 41 countries. Now, for the first time, findings are available about how a certain group of potential future decision-makers currently perceives the 17 goals. From this, specific recommendations can be derived for university education.
FRANKFURT. In 2015, the member states of the United Nations adopted the 2030 Agenda for Sustainable Development. The central element is the 17 Sustainable Development Goals (SDGs). These include “Zero Hunger", “Clean Water", “Responsible Consumption" and “Life Below Water". The SDGs relate to all three pillars of sustainability, i.e. social, economic and environmental sustainability. Achieving the goals should enable a life of dignity for everyone worldwide and conserve the planet's natural resources on a sustained basis. Yet how are the SDGs perceived in the first place, and what conclusions can be drawn from this? Until now, there has been a research gap in this area. The few international studies to date had mostly interviewed rather broad population groups. There was a lack of data that could deliver specific recommendations in certain realms of society, for example, how university practice could be improved in line with the 2030 Agenda.
A new study by Goethe University Frankfurt is now closing this research gap. It is based on an online survey in 41 countries in North America, South America, Africa, Asia, Oceania and Europe, which was conducted between September 2020 and July 2021. All 4,305 interviewees were exclusively students of environment-related subjects, such as environmental science, biology or nature management. They indicated on a scale of 1 to 5 how important they considered each individual SDG. “Our study is the first to document and evaluate how the UN's Sustainable Development Goals are perceived among such a highly selected group of future decision-makers," says first author Dr Matthias Kleespies from the Department of Didactics in the Biological Sciences and Zoo Biology at Goethe University Frankfurt.
The data show, says Kleespies, that the SDGs have a high level of acceptance among environmental students worldwide, irrespective of the region. For Kleespies, this is a pleasing result: “The major social, economic and environmental problems we're currently facing worldwide are also perceived as such."
Through factor analysis, a common statistical method, Kleespies was able to establish something else: the interviewees mainly assigned individual SDGs to only one of the three pillars of sustainability: for example, the goal “No Poverty" exclusively to the first pillar (social) or the goal “Climate Action" exclusively to the third pillar (environmental). These assignments led to a further result, says Kleespies: “We could see significant differences between countries in how they rate the three pillars." For example, interviewees from Germany considered the environmental pillar to be particularly important, while interviewees from Thailand rated all three pillars as more or less equally important.
To be able to evaluate the differences between countries even more accurately, a further statistical analysis followed: the results from the individual countries were compared with five prosperity indicators, including the Human Development Index (HDI) and the Environmental Performance Index (EPI). A similar picture emerged for all five indicators. In a direct comparison, countries with lower indices – such as the Philippines – rated the SDGs as more important than countries with higher indices did, such as Canada. “This result surprised us, as older studies often showed that especially people in modern industrialised societies campaign more for environmental protection," says Kleespies.
Even if the study is not transferable to a country's entire population, it does, according to Professor Paul Dierkes, head of the Department of Didactics in the Biological Sciences and Zoo Biology, deliver important new insights. “To be able to put the SDGs into practice in a country, there needs to be great acceptance not only among the population but also among the people at the social and political interfaces. As potential future decision-makers and multipliers, students in the environmental domain are particularly important in this context. Although a university education in this field is no guarantee of a decision-making position, universities teach important skills, abilities and knowledge that qualify for such positions."
What improvement measures for university education can be derived from the study? Kleespies says: “Degree programmes in the environmental sciences ought to address in greater depth the fact that the SDGs are multidimensional and that each of the goals contains a social, environmental and economic component." After all, he says, the study has shown that students mostly overlook this multidimensionality. For example, SDG 15 – “Life On Land" – was often categorised as a solely environmental goal. “But protecting terrestrial ecosystems also includes very important economic and social components." A second suggestion is directed specifically at more affluent countries, where the SDGs were rated as less important by comparison. Kleespies calls on the universities there to incorporate educational measures on the UN's Sustainable Development Goals into the present curriculum of degree programmes: “In this way, students will be better informed than they are at the moment about the benefits and multidimensional nature of the SDGs."
Over 4,000 students took part in the online survey and emails were sent to institutes in more than 50 countries. For 41 countries, the datasets were ultimately sufficient for a statistical analysis.
Publication: “The importance of the Sustainable Development Goals to students of environmental and sustainability studies – a global survey in 41 countries", Matthias Winfried Kleespies & Paul Wilhelm Dierkes; https://doi.org/10.1057/s41599-022-01242-0
Department of Didactics in the Biological Sciences and Zoo Biology
Goethe University Frankfurt
Dr Matthias Kleespies
Tel.: +49 (0)69 798-42276
Professor Paul W. Dierkes
Tel.: +49 (0)69 798-42273