Frankfurt researchers have explained the mechanism of regulator SidJ in detail / Accelerated publication in Nature
FRANKFURT. In order to control cellular processes and thwart the immune system, the bacterium Legionella pneumophilia, the cause of the notorious Legionnaires' disease, releases hundreds of enzymes. Biochemists at Goethe University have now elucidated important details in the interaction of bacterial effectors. They discovered how the regulatory enzyme SidJ keeps other dangerous virulence factors in check.
The incidence of Legionnaires' disease has increased in the past two decades. The natural habitat of Legionella is freshwater biotopes, where they mainly reproduce in amoebae. In addition, Legionella can also colonize water tanks or pipes and spread, for example, via poorly maintained air-conditioning systems. Contaminated aerosols are released into the air and trigger the infection. The pathogens cause, among others, pneumonia, which is often fatal in elderly patients or individuals with a weak immune system.
What makes Legionella so dangerous is its ability to multiply in phagocytes of the immune system by secreting virulence factors. Some of these effectors – the enzymes of what is known as the SidE family – are so toxic that without tight control they would instantly kill their host cells. However, since Legionella needs the host cells in order to multiply, it has developed a sophisticated mechanism for the precise metering of SidE enzyme activity. Details of this process are now reported by scientists at Goethe University and from Grenoble in the journal Nature.
They have shown that the regulator SidJ also released by Legionella works as an antidote to SidE enzymes, thus ensuring accurate control of SidE activity. The SidJ regulator is a glutamylase, i.e. it has a rare enzyme activity that allows amino acid glutamates to be linked together to form chains. In this case, SidJ attacks the central glutamate of SidE enzymes and inhibits their activity. So far, little is known about glutamylases – so the scientists were all the more surprised when they discovered that it is precisely this type of enzyme which is important for the coordinated interaction of the virulence factors of Legionella.
“This is a typical example of how completely unpredictable results drive research. Such discoveries are what make science such a fascinating and exciting profession," says Professor Ivan Dikic from the Institute of Biochemistry II and the Buchmann Institute for Molecular Life Sciences at Goethe University. “We can only gain a molecular understanding of the complex world of bacterial infections by working in interdisciplinary teams and combining methods from modern biochemistry and proteomics with cell and structural biology techniques."
The researchers also revealed how SidJ is activated in host cells: It requires the calcium-binding protein calmodulin found in mammalian cells. Cryo-electron microscopy played an important role in explaining the structure of the calmodulin-SidJ complex. “Glutamylation as a protein modification is understudied. Our finding that Legionella pneumophilia uses exactly this mechanism to sustain the infection certainly argues for more research in this field. For example, the extent to which Legionella utilizes this modification to regulate other cellular processes is completely unclear," explains Dr. Sagar Bhogaraju, who led the microscopic examinations at the European Molecular Biology Laboratory (EMBL) in Grenoble.
This so far unknown mechanism opens up new possibilities for research to inhibit the spread of Legionella in the host organism. “We're currently working on eliminating SidJ selectively by developing inhibitors for the glutamylase domain. In addition to the use of antibiotics, they could prevent the spread of Legionella pneumophilia in phagocytes," explains Dikic.
Publication: Sagar Bhogaraju, Florian Bonn, Rukmini Mukherjee, Michael Adams, Moritz M. Pfleiderer, Wojciech P. Galej, Vigor Matkovic, Sissy Kalayil, Donghyuk Shin, Ivan Dikic: Inhibition of SidE ubiquitin ligases through SidJ/Calmodulin catalyzed glutamylation, in Nature 22. Juli 2019 DOI: 10.1038/s41586-019-1440-8 https://www.nature.com/articles/s41586-019-1440-8
Further information: Professor Ivan Dikic, Institute of Biochemistry II, Niederrad Campus, and Buchmann Institute for Molecular Life Sciences, Riedberg Campus, Tel.: +49(0)69-6301-5964, Email: email@example.com.
New insights into ribosome recycling with enzyme ABCE1
Ribosomes are molecular machines that produce proteins in cells. Having finished the job, the ribosomes need regenerating. This process is important for the quality of the proteins produced and thus for the whole cell homeostasis as well as for developmental and biological processes. Biochemists from Goethe University Frankfurt together with biophysicists at LMU Munich have now watched one of the most important enzymes for ribosome recycling at work – ABCE1 – and shown that it is unexpectedly versatile in terms of structure.
Ribosomes decode the genetic information from the messenger RNAs and translate it into proteins. Once they have produced a protein, but also if defective proteins have come to a halt in the ribosome, the ribosomes have to be “recycled" so that they are in good working order for a new round of synthesis. In all organisms (except bacteria), the enzyme ABCE1 coordinates this process, in which the ribosome is split into its two subunits. Biochemist Robert Tampé and LMU biophysicist Thorben Cordes, in collaboration with researchers at the University of Groningen (Netherlands), have shown that ABCE1 adopts three structural conformations to boost recycling. Their results are presented in the current issue of the journal Cell Report.
The ABCE1 enzyme can split ATP, the energy currency of cells, and use the energy released to separate the two ribosomal subunits. “Recent structural and functional data have shown that a conformational change of the enzyme, that is, a change in its spatial structure, is essential within this process for the diverse functions of ABCE1," says Cordes. Using an integrated test approach – among others with the help of what is known as the single-molecule FRET method – his team has now observed at first hand the structural variability of ABCE1 at the level of single molecules.
In the course of this work, the researchers established that the two ATP binding sites of ABCE1 can adopt three conformations – open, intermediate and closed – which are in a state of dynamic equilibrium. Interaction of ABCE1 with both the ribosome and the ATP influences the structural dynamics of the two ATP binding sites. This results in a complex network of different states, in which ribosome and ATP shift the equilibrium in the direction of the closed conformation.
“We assume that the conformations perform functionally different roles in the dissociation of the ribosome as well as for the many other diverse functions of ABCE1," says Cordes. “Ribosome recycling is governed by an extraordinarily complex and conserved machinery, which has medical significance as yet unimagined," adds Robert Tampé.
Cell Reports 2019
Publication: Giorgos Gouridis, Bianca Hetzert, Kristin Kiosze-Becker, Marijn de Boer, Holger Heinemann, Elina Nürenberg-Goloub, Thorben Cordes, Robert Tampé: ACBE1 controls ribosome recycling by an asymmetric dynamic conformational equilibrium, in: Cell Reports 2019 DOI: 10.1016/j.celrep.2019.06.052 https://doi.org/10.1016/j.celrep.2019.06.052
Further information: Professor Robert Tampé, Institute of Biochemistry, Faculty of Biochemistry, Chemistry and Pharmacy, Riedberg Campus, Tel.: +49(0)69-798-29475 , Email: firstname.lastname@example.org, www.biochem.uni-frankfurt.de
Image material can be downloaded under: http://www.uni-frankfurt.de/80584137
Caption: Three states of nucleotide binding sites can be seen in the histogram: open, intermediate and closed. Image: T. Cordes, LMU Munich
Study shows: MRI on par with cardiac catheterization
FRANKFURT. The non-invasive measurement of blood flow to the heart using magnetic resonance imaging (MRI) is on par with cardiac catheterization. This was the result of an international study published in the current issue of the New England Journal of Medicine and headed by researchers from Goethe University.
For patients with chest pain and presumably stable coronary heart disease (CHD), therapy depends primarily on how constricted the arteries that support the heart are (coronary arteries). This is often determined using an invasive procedure called cardiac catheterization. If necessary, the pressure in the coronary arteries is also measured. The combination of these methods is the currently the recognized standard for making therapy decisions. Cardiovascular magnetic resonance imaging (MRI) is an alternative for directly measuring the blood flow in the myocardium.
In contrast to cardiac catheterization, MRI is non-invasive, works without ionising radiation, can be done in 40 minutes and delivers direct measurements of the blood flow to the heart. The team headed by Professor Eike Nagel, Director of the Institute for Experimental and Translational Cardio Vascular Imaging at Goethe University was able to demonstrate that MRI measurements are as safe to guide decision-making as the currently used invasive procedure. Within the international MR-INFORM study, they examined 918 patients with an indication for cardiac catheterization to see if decision-making by an MRI scan led to the same results as the current invasive method.
Patients were randomly assigned to two groups. One group received the standard diagnostic investigation with cardiac catheterization and pressure measurement of the coronary arteries. The other had the 40 minute MRI scan of the heart to decide whether to send the patient on for invasive angiography.
In each study arm, constricted coronary vessels were dilated when indicated by the examination. In the following year, the physicians documented how many patients died, suffered a heart attack or required a repeated vascular dilation. In addition, they recorded whether the heart symptoms continued.
The result: in the group of patients examined by MRI, less than half required a diagnostic cardiac catheterization and fewer patients received a vascular dilation (36% vs 45 %). This means that with a fast and non-invasive MRI examination as the first test, both diagnostic and therapeutic cardiac catheterizations can be reduced. Importantly, the two groups did not differ in terms of continuing symptoms, the development of new symptoms, complications, or deaths.
“This means that patients with stable chest pains who previously would have received cardiac catheterization can alternatively be examined with MRI," concludes Professor Eike Nagel. “The results for the patients are just as good, but an examination by MRI has many advantages: the procedure takes about 40 minutes, patients merely receive a small cannula in their arm and are not subject to radiation." The physician hopes that the less invasive method will now be used as a method of first choice, reducing the need for cardiac catheterizations.
In contrast to Great Britain, where an MRI scan of the heart is paid for by the National Health Service (NHS), reimbursement is often difficult in Germany and usually has to be negotiated individually. In this regard, Nagel also hopes that the study will contribute to the acceptance of the non-invasive procedure and improve its availability.
Financial support was provided primarily by the British National Institute of Health Research (NIHR) via the Biomedical Research Centre (BRC) at Guy's & St. Thomas' Hospital, the German Centre for Cardiovascular Research (DZHK) and the company Bayer AG Deutschland.
A picture can be downloaded here: http://www.uni-frankfurt.de/78920068
Caption: Measuring blood flow in the myocardium with magnet resonance imaging (top). The dark area in the myocardium (arrows) shows a pronounced reduction of blood flow. The cardiac catheterization of the same patient (bottom) shows a clear constriction of the artery. Credit: Eike Nagel, Goethe University
Publication: Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease Eike Nagel, et al., N Engl J Med 2019;380:2418-28. DOI: 10.1056/NEJMoa1716734
Further information: Professor Eike Nagel, Institute for Experimental and Translational Cardiovascular Imaging, Faculty of Medicine, Niederrad Campus, Tel.: +49 151 4197 4195, email@example.com
Researchers simulate the extreme pressure and heat in the Earth’s mantle
FRANKFURT. Unlike flawless gems, fibrous diamonds often contain small saline inclusions. These give hints to scientists about the conditions under which diamonds are formed deep in the Earth's mantle. A research team including scientists from Goethe University solved the puzzle of the formation of these inclusions by simulating conditions of extreme heat and pressure in the laboratory.
Diamonds are crystals of carbon that form deep in the Earth's mantle underneath the oldest continents, the cratons. They are transported to the surface of the earth in exotic magmas called kimberlites by explosive volcanic eruptions. Previous studies had always determined that diamonds include fluids containing sodium and potassium, but the origin of these fluids was unknown.
“In order for these inclusions to form, parts of the Earth's oceanic crust and their sediment layer had to be submerged beneath the cratonic continents in what is known as a subduction zone. These zones are located at depths of over 110 kilometres at a pressure of over four gigapascals, or 40 thousand times the atmospheric pressure," explains Michael Förster, the first author of the study that was published in the scientific journal Science Advances. The submergence of the earth's crust has to happen quickly so that the diamond can form before the sediment starts to melt at temperatures over 800 degrees Celsius, and react with the cratonic mantle.
For the high-pressure experiment in the laboratory, scientists from Sydney, Mainz and Frankfurt stacked marine sediment and peridotite (rocks from the Earth's mantle) in four-millimetre capsules and placed them under high pressure and extreme temperatures. At pressures of four to six gigapascals – corresponding to depths of 120 to 180 kilometres – small salt crystals formed from the reaction between the two layers. Their potassium to sodium ratio corresponded exactly to the saline fluid inclusions in diamonds. In experiments with less pressure, corresponding to depths of less than 110 kilometres, these salts were not present. Instead, potassium was absorbed from the recycled sediment by mica.
“Unlike previous models that attributed the source of the salts to seawater, the sediments represent a plausible source of potassium," says the mineralogist Professor Horst Marschall from Goethe University. “The potassium concentration in seawater is too low to explain the saline inclusions in diamonds." Magnesium-rich carbonates, important components of the kimberlites, also came about as a by-product of the reaction.
Publication: Michael W. Förster, et al. Melting of sediments in the deep mantle produces saline fluid inclusions in diamonds, in Science Advances, Vol.5 No. 5, DOI: DOI: 10.1126/sciadv.aau2620; https://advances.sciencemag.org/content/5/5/eaau2620
A picture may be downloaded here: http://www.uni-frankfurt.de/78861524
Caption: Prof. Horst Marschall in front of one of the high-pressure belt apparatus in the Institute for Geosciences used to simulate the formation of inclusions in diamonds. Credit: Horst Marschall, Goethe University
Further information: Professor Horst Marschall, Wilhelm Heraeus Professor for Deep-Earth Processes, Institute for Geosciences, Faculty 11, Riedberg Campus, phone: +49 69 798- 40124 , firstname.lastname@example.org
The famous philosopher returns to Goethe University on the occasion of his 90th birthday to talk about the relationship between morality and ethics
FRANKFURT. Jürgen Habermas is the most important contemporary German philosopher and one of the most frequently cited intellectuals worldwide. He played a decisive role in shaping the political debates in the Federal Republic of Germany. On the occasion of his 90th birthday, Habermas will return to Goethe University, where he carried out his research and taught until his retirement. The programme includes a public lecture in German by Habermas with the title:
“Noch einmal: Zum Verhältnis von Moralität und Sittlichkeit“
(Once more: on the relationship between morality and ethics)
On Wednesday, 19th June 2019 at 6:00 p.m.
In the Hörsaalzentrum (HZ 1) on Westend Campus at Goethe University,
Theodor-W.-Adorno-Platz 5, 60323 Frankfurt am Main.
In his lecture, Jürgen Habermas takes up a central issue in the field of practical philosophy and one that plays a significant role in his work. Starting from the controversy between Kant and Hegel, he asks how the principles of moral and political autonomy behave with regard to the “ethical" reality of historically situated communities. He argues that the principles of justice have priority over the imperatives of social integration and from this draws conclusions for our present day.
Jürgen Habermas will celebrate his birthday the day before (18th June), and will then come to Frankfurt following an invitation by Professor Rainer Forst and Professor Klaus Günther, speakers of the Cluster if Excellence “The Formation of Normative Orders" at Goethe University. The Leibniz research group at Goethe University “Transnational Justice", headed by Professor Forst, was also involved in organizing the lecture.
Goethe University President Professor Birgitta Wolff said, “Jürgen Habermas is one of the most influential personalities of Goethe University and contemporary philosophy. His discourse theory also inspired the Cluster of Excellence 'The Formation of Normative Orders', which has led to further current research initiatives such as the Frankfurt contribution to the “Institute for Societal Cohesion'."
Professor Rainer Forst, political philosopher, stated “It's is a great honour and pleasure for us to welcome Jürgen Habermas at Goethe University on the occasion of his birthday. His discourse theory has been paradigm shaping in the fields of philosophy, law, and the social sciences. No one considering the most urgent challenges of our day, such as global justice, religiously pluralistic societies, or questions of cosmopolitan democracy and state citizenship can bypass his work."
Jürgen Habermas had three separate stays in Frankfurt, where in his own words he experienced “the most exciting times" of his “adult life". He worked as assistant at the Institute for Social Research with Theodor W. Adorno from 1956 to 1959. As successor to Max Horkheimer, he held the double chair for philosophy and sociology at Goethe University from 1964 to 1971.
Following his time at the Max-Planck-Institut zur Erforschung der Lebensbedingungen der wissenschaftlich-technischen Welt (Max Planck Institute for the research of living conditions in scientific-technical world) in Starnberg, where he still lives today, he again followed a summons to Frankfurt despite attractive alternative offers from the U.S. and other places. Here, he carried out research and taught as professor for philosophy with a focus on social philosophy from 1983 until his retirement in 1994.
The Gottfried Wilhelm Leibniz Prize is among the many awards and distinctions Jürgen Habermas has received over his lifetime. This is still the most important and best endowed national science prize and Habermas received it in 1986, the year it was first awarded by the German Research Foundation (DFG). He used the funds to establish a legal-philosophical research group the “AG Rechtstheorie" (Legal Theory Working Group). Rainer Forst and the legal scholar Klaus Günther were among its members.
The lecture will be opened by Goethe University President Professor Birgitta Wolff, followed by welcoming words from Ayse Asar, State Secretary of the Hessian Ministry of Higher Education, Research and the Arts, and from Professor Rainer Forst.
Media representatives and the interested public are warmly welcome to attend. The lecture will be in German.
During an internal conference at Goethe University in the following days, former students and colleagues of Jürgen Habermas will discuss his work with him, in particular his new book to be published in the fall.
Please note: The organisers regret that interview requests with Professor Habermas cannot be accommodated.