News Article | November 15, 2016
FRANKFURT. Translation of the genetic code in proteins is a central process in life and takes place in the ribosome, a giant molecule consisting of two subunits. This is where long chains of amino acids are formed like on an assembly line. An interdisciplinary research group from Goethe University Frankfurt, the EMBL in Heidelberg, and the Gene Center of the University of Munich (LMU) has now succeeded in solving the structure of a central player in this process bound to the small ribosomal subunit: the protein containing a unique iron-sulphur domain with the nickname "Iron Hammer" splits the two subunits of the ribosome when a protein chain is completed so that production of a new protein can begin. The two subunits of the ribosome have to be actively split once the protein chain is complete otherwise errors occur in mRNA translation: research ignored this fact for a long time. Central player in this "ribosome recycling" process is the essential and highly dynamic metalloenzyme ABCE1. The iron-sulphur domain of ABCE1, known as the "Iron Hammer", rotates and presses the ribosomal subunits apart like a lever. To uncover this, the research group led by Professor Robert Tampé at the Institute of Biochemistry at Goethe University Frankfurt isolated a complex of the small ribosomal subunit with ABCE1 (post-splitting complex) by means of an innovative preparation method. This complex was chemically fixed and cut into pieces, while the original distance information was preserved. At the EMBL in Heidelberg, the researchers used highly advanced mass spectrometry to analyse these small fragments and relate them to each other revealing their original distances on nanometre scale. The group in Munich then examined the reconstructed complex with a high-resolution cryogenic electron microscope and was able to reconstruct a 3D model of the post-splitting complex with tightly bound ABCE1 from a vast collection of single-particle images. Professor Robert Tampé summarizes the significance of these results: "We have forced the rebellious and aggressive multi-domain enzyme ABCE1 into a new, unexpected state on the ribosome and used the combined expertise of three institutes to enrich textbook knowledge for coming generations of students."
News Article | January 21, 2016
Scientists at the Helmholtz Zentrum München, working with colleagues from the Ludwig-Maximilians-Universität München, have developed a method for the thorough analysis of protein modifications. They mapped the phosphorylation sites of the RNA polymerase II enzyme, which is responsible for expressing our genes. The results have now been published in the Molecular Cell scientific journal. The contents in our genetic information are actually silent (meaning inactive) and first have to be made to "speak". Like the read head in a tape recorder, RNA polymerase II, Pol II for short, runs over the DNA (tape) and transcribes the genetic and epigenetic information into RNA. In order to keep the enzyme from working randomly, however, it is dynamically modified at many different points in order to control its activity depending on the situation. "Phosphorylation makes it possible to influence the activity of the enzyme at 240 different sites," explains Prof. Dirk Eick, the study's last author and head of the Research Unit Molecular Epigenetics at Helmholtz Zentrum München. Together with colleagues from the Biomedical Center and Gene Center of the Ludwig-Maximilians-Universität München and the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, he and his team have developed a method for simultaneously examining all 240 sites in Pol II. "The trick is a combination of genetic and mass spectrometric methods," reveals first author Dr. Roland Schüller. "By producing genetically modified variants of the regions in question, we can examine each individual phosphorylation site with a mass spectrometer." This allows the researchers to determine exactly how and precisely where certain enzymes that influence phosphorylation act. The scientists also successfully compared the Pol II modification patterns in humans and in yeast. "The regulation of the transcription of genes by Pol II is an elementary process in life and gene regulation deviations are the basis for many human disorders," study leader Eick explains the work's background. "Research into the phosphorylation pattern at certain times during the transcription cycle is therefore necessary in order to be able to gain an understanding of the underlying mechanisms of gene regulation at the transcription level sometime in the future." Explore further: Lab identifies new role for factor critical to transcription More information: Schüller, R. et al. (2015). Heptad-specific Phosphorylation of RNA Polymerase II CTD, Molecular Cell, DOI: 10.1016/j.molcel.2015.12.003
News Article | December 14, 2016
The latest recipients of Germany's most prestigious research funding prize have been announced. In Bonn today, the Joint Committee of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) chose ten researchers, three women and seven men, to receive the 2017 Leibniz Prize. The recipients of the prize were selected by the Nominations Committee from 134 nominees. Of the ten new prizewinners, three are from the natural sciences, three from the humanities and social sciences, two from the life sciences and two from the engineering sciences. Each of the ten winners will receive €2.5 million in prize money. They can use these funds for their research work in any way they wish, without bureaucratic obstacles, for up to seven years. The awards ceremony for the 2017 Leibniz Prizes will be held on 15 March in Berlin. The following researchers will receive the 2017 "Funding Prize in the Gottfried Wilhelm Leibniz Programme" awarded by the DFG: The Gottfried Wilhelm Leibniz Prize has been awarded by the DFG annually since 1986. Each year a maximum of ten prizes can be awarded, each with prize money of €2.5 million. With the ten prizes for 2017, a total of 348 Leibniz Prizes have been awarded to date. Of these, 115 were bestowed on researchers in the natural sciences, 101 in the life sciences, 79 in the humanities and social sciences, and 53 in the engineering sciences. The number of award recipients is higher than the number of awarded prizes because, in exceptional cases, the prizes and money can be shared. Accordingly, a total of 374 nominees have received the prize, including 326 men and 48 women. The Leibniz Prize is the most significant research prize in Germany. Seven past prizewinners have subsequently received the Nobel Prize: 1988 Professor Dr. Hartmut Michel (Chemistry), 1991 Professor Dr. Erwin Neher and Professor Dr. Bert Sakmann (Medicine), 1995 Professor Dr. Christiane Nüsslein-Volhard (Medicine), 2005 Professor Dr. Theodor W. Hänsch (Physics), 2007 Professor Dr. Gerhard Ertl (Chemistry) and most recently in 2014 Professor Dr. Stefan W. Hell (Chemistry). Professor Dr. Lutz Ackermann (43), Organic Molecular Chemistry, Institute of Organic and Biomolecular Chemistry, University of Göttingen Lutz Ackermann has been selected for the 2017 Leibniz Prize for his outstanding work in the field of organic chemistry. His international reputation is based especially on his research into the catalytic activation of carbon-hydrogen bonds. These bonds, which occur in all organic substances, are usually extremely inert and permit only very poor and frequently non-selective transformation. The methods developed by Ackermann and his colleagues have paved the way for fundamentally new and low-impact manufacturing methods for important chemical products including active substances, agrochemicals and fine chemicals. Through his other work, Ackermann has also created new concepts for environmentally friendly chemical synthesis. Lutz Ackermann studied chemistry in Kiel, and, after further studies in Rennes and Mülheim an der Ruhr, he obtained his doctorate from the University of Dortmund. He did postdoctoral research at Berkeley before going to Munich in 2003 to work as the leader of a DFG-funded Emmy Noether independent junior research group. Ackermann has held his current chair in Göttingen since 2007 and has headed the Institute of Organic and Biomolecular Chemistry there since 2015. He is one of the most frequently cited researchers in his field in the world. Professor Dr. Beatrice Gründler (52), Arabic Studies, Seminar for Semitic and Arabic Studies, Free University of Berlin Beatrice Gründler will receive the Leibniz Prize for her studies on the diversity of voices in Arabic poetry and culture. She has been interested in the medium of script and its fundamental importance to Arabic traditions since an early stage in her career, as evidenced for example by her book "The Development of the Arabic Script" (1993). Through her research she has developed a complex media history of the Arab world, from the introduction of paper to book printing and beyond - indeed, she refers to an 'Arabic book revolution'. In a pilot project for a critical, annotated digital edition of the "Kalila wa-Dimna", begun in 2015, Gründler has unravelled the history of the text, development and impact of this collection of fables, considered one of the earliest Arabic prose works and a central text of Arabic wisdom literature. Gründler's own approach puts into practice in an exemplary way the encounters between Arabic and European knowledge traditions that she investigates in her work - another reason for the importance of her research. Beatrice Gründler studied at Strasbourg, Tübingen and Harvard, where she received her doctorate in 1995. After a period at Dartmouth College, she began teaching at Yale University in 1996, first as an assistant professor and from 2002 as Professor of Arabic Literature. In 2014 she returned to Germany, and has since been undertaking research at the Free University of Berlin. Ralph Hertwig will be recognised with the 2017 Leibniz Prize for his pioneering work in the psychology of human judgement and decision-making. His research has expanded our understanding of the possibilities and limitations of human rationality. Hertwig investigates the strategies which humans use, faced with limited knowledge, limited cognitive resources and often limited time, to nonetheless make good decisions and organise their actions. Central to his work is the question why a limitation also constitutes a strength, in other words how adaptive heuristics, as simple rules of thumb for problem-solving, can be as effective as complex optimisation models. Another of Hertwig's important contributions to decision research is the distinction between experience-based and description-based assessment of risk. This explains why the dramatic consequences of climate change, for example, are systematically underestimated by society, because although there is plenty of information available to describe the problem, there is little everyday experience - the main thing that people base their decisions on. Ralph Hertwig has been the director of the Max Planck Institute for Human Development since 2012 and heads the Center for Adaptive Rationality. Hertwig began his scientific career in 1995 at the Max Planck Institute for Psychological Research in Munich. In 1997 he moved to the Max Planck Institute in Berlin. Between 2000 and 2002 he was a Research Fellow at Columbia University. In 2003 he obtained his habilitation from the Free University of Berlin. In 2005 he was appointed Professor of Cognitive Science and Decision Psychology at the University of Basel, and moved from there to his current position. Karl-Peter Hopfner will receive the Leibniz Prize for his outstanding work in structural molecular biology and genome biology, with which he has made pioneering contributions to the field of DNA repair and the cellular detection of foreign nucleic acids. Hopfner's research focused on the molecular mechanisms of multiprotein complexes, which play an important role in the detection of damaged or viral nucleic acids. These detection processes are crucial to the protection of the genome; errors in detection and repair are among the main reasons for the development of cancer. Building on that work, Hopfner has carried out essential work on DNA double-strand break repair and in recent years has decoded the mechanism of the central MRN complex Mre11-Rad50-Nbs1, a DNA damage sensor. He also contributed substantially to answering the question of how cellular sensors of the innate immune system recognise viral or bacterial nucleic acids in the case of infection. Here, the sensors must distinguish between the body's own RNA and foreign RNA. Karl-Peter Hopfner studied biology in Regensburg and in St. Louis, USA. He completed his doctorate at the Max Planck Institute for Biochemistry in Martinsried as part of the Division led by Nobel Prize winner Robert Huber. Between 1999 and 2001 he carried out postdoctoral research at the Scripps Research Institute in La Jolla, before accepting a tenure track professorship at the Gene Center at LMU Munich. He has been a full professor at LMU since 2007. Professor Dr. Frank Jülicher (51), Theory of Biological Physics, Max Planck Institute for the Physics of Complex Systems, Dresden The award of the Leibniz Prize to Frank Jülicher recognises a world-leading researcher in biophysics with the ability to identify universal physical principles in the complex world of living matter. He had already attracted attention with his early work on the physics of hearing and cell mechanics. Through his investigation of active matter - the components of which exhibit autonomous activity, such as molecular motors, which play a key role in cell movement and division - Jülicher has established a new field of research. This raises many fundamental questions in non-equilibrium physics and has also inspired numerous new applications as well as biomimetic design. In collaboration with French researchers, the biophysicist laid the foundations for the dynamics of active matter by formulating a general hydrodynamic theory of active matter. Most recently, Jülicher has turned his attention to the control and organisation of cells in tissue. His seminal work is contributing to our understanding of cell self-organisation in tissue. This phenomenon, as yet poorly understood, is of enormous importance to developmental biology and medical applications. Frank Jülicher studied physics in Stuttgart and Aachen, received his doctorate in Cologne in 1994 and then spent two years researching in the USA and Canada. He subsequently worked with leading researchers in Paris in the field of soft matter and biophysics, before obtaining his habilitation in 2000 at Paris Diderot University (Paris 7). Since 2002, Jülicher has been the director of the Max Planck Institute for the Physics of Complex Systems in Dresden and Professor of Biophysics at the Technical University of Dresden. Professor Dr. Lutz Mädler (45), Mechanical Process Engineering, Stiftung Institut für Werkstofftechnik (IWT) and Department of Production Engineering, University of Bremen Lutz Mädler will receive the Leibniz Prize in recognition of his pioneering work in the targeted reactive formation of nanoparticles in the gas phase and their effect on living matter. He has developed an improved variant of flame spray pyrolysis for the cost-effective synthesis of nanoparticles, involving the thermochemical splitting of organic compounds. His work has made flame spray pyrolysis available for industrial applications. Mädler subsequently refined this pyrolysis technique when he discovered the droplet explosion phenomenon in flame sprays and its effects on material synthesis. However, as well as looking at the tailored synthesis of nanoparticles, Mädler has also investigated how toxic these particles are to the human body. This is important because many applications, for example paints, textiles and dental fillings, have direct impacts on humans. Mädler was able to demonstrate that interactions between synthetic nanoparticles and biological tissue produce reactive oxygen species which can trigger undesirable reactions. Lutz Mädler studied physics at the Technical University of Zwickau and then process engineering at Technische Universität Bergakademie Freiberg, where he obtained his doctorate in 1999. He completed his habilitation at ETH Zurich and then, with the support of a DFG fellowship, became a Senior Researcher at the University of California, Los Angeles. In 2008 he was appointed professor at the University of Bremen. Britta Nestler has been selected to receive the 2017 Leibniz Prize for her significant, internationally recognised research in computer-assisted materials research and the development of new material models with multiscale and multiphysical approaches. Nestler has developed extremely flexible and high-performing simulation environments to simulate the microstructure of materials for use on supercomputers. These are based on her own quantitative models for the description of multicomponent systems. She has thus achieved a new quality of microstructure representation in the thermomechanical simulation of materials and the simulation of solidification processes and thus depicted these processes through realistic 3D simulation for the first time. Through her creative application and further development of the phase field method, Nestler has achieved outstanding fundamental insights which are also of enormous practical relevance. For example, her simulation calculations are used to predict the spread of cracks in design materials such as brake discs and therefore help to extend their lifetime. Britta Nestler studied physics and mathematics in Aachen, where she also received her doctorate. Research visits took her to Southampton, UK and Paris. In 2001 Nestler accepted a professorship in the Faculty of Computer Science at Karlsruhe University of Applied Sciences and in 2009 her current chair at KIT. Professor Dr. Joachim P. Spatz (47), Biophysics, Max Planck Institute for Intelligent Systems, Stuttgart, and Institute of Physical Chemistry, University of Heidelberg Joachim Spatz will be recognised with the Leibniz Prize for his outstanding research at the boundaries of materials sciences and cell biophysics. His research is concerned with cell adhesion, that is, the adhesion and bonding of cells to one another and to surfaces. His exemplary experimental approach has garnered precise insights into the control of cell adhesion and indeed physiological processes. To achieve this, Spatz used artificial, molecularly structured boundary surfaces to reduce possible interactions to a minimum of molecular components. Joachim Spatz' scientific achievement lies in the fact that he can study the communication mechanisms between cells in a new way with the help of concepts from materials science and physics. Using these resources, he was able to explain how the molecular mechanism of collective cell migration works in wound healing. Joachim Spatz studied physics in Ulm and at Colorado State University. He obtained his doctorate in macromolecular chemistry in Ulm, and it was also there that he completed his habilitation with a topic on cell mechanics. Since 2000 he has been a professor of biophysical chemistry in Heidelberg. In 2004 he was appointed director of the Max Planck Institute for Metals Research, now the Max Planck Institute for Intelligent Systems, in Stuttgart. Since 2008 he has also held a visiting professorship in molecular cell biology at the Weizmann Institute in Rehovot, Israel. Professor Dr. Anne Storch (48), African Studies, Institute for African Studies and Egyptology, University of Cologne In awarding the 2017 Leibniz Prize to Anne Storch, the DFG is honouring an extremely innovative and world-renowned researcher in African Studies who has contributed to a far-reaching reorientation of her field through her pioneering work. Drawing on questions and methods from cultural anthropology and the social sciences, Storch has introduced new thematic and methodological dimensions, both theoretical and practical, to African Studies. Her exemplary studies have also shown how linguistically based analyses can be used in an interdisciplinary approach to develop a cultural-anthropological understanding of contemporary Africa. Of particular significance was her study of taboos and secret languages in central Africa, published in 2011, which describes linguistic observations in such a way that they lead to complex sociological descriptions of power practices and political mechanisms of effect. Storch's case studies, rooted in, yet transcending, linguistic speech description, have become internationally significant model studies for a modern, self-critical approach to African Studies. Anne Storch has been Professor of African Studies in Cologne since 2004. She trained in anthropology, African Studies, Oriental Studies and archaeology in Frankfurt am Main and Mainz. Between 2006 and 2009 she served as president of the Fachverband Afrikanistik, the specialist society for Africa-related scholarship in Germany. Since 2014 she has been the president of the International Association for Colonial and Postcolonial Linguistics. Awarding the Leibniz Prize to Jörg Vogel recognises one of the world's leading researchers in the field of ribonucleic acid biology. He was selected for his pioneering contributions to our understanding of regulatory RNA molecules in infection biology. Vogel recognised the importance of RNA biochemistry in prokaryotes very early on and has done pioneering work in the application and development of high-throughput sequencing for RNA analysis. Using this method, he has studied the influence of pathogens on the host cell. Vogel has also discovered how small regulatory RNA molecules control protein synthesis and the breakdown of RNA. This in turn has contributed to the development of new methods which can be used in gene therapy. Together with Emmanuelle Charpentier, who won the Leibniz Prize in 2016, Vogel was able to understand tracrRNA (trans-activating RNA) and its function, which made the application of the CRISPR/Cas9 system possible. Vogel thus uncovered general biological principles which play a major role in our understanding of pathogenic microorganisms and are resulting in new treatment approaches. Jörg Vogel studied biochemistry at the Humboldt University of Berlin, where he also obtained his doctorate on RNA splicing in plants. After doing postdoctoral research in Uppsala and Jerusalem, in 2004 he was appointed Head of Division at the Max Planck Institute for Infection Biology in Berlin. Since 2009 he has been a professor at the University of Würzburg, where he heads the Institute for Molecular Infection Biology. The Leibniz Prizes will be awarded on 15 March 2017 at 3.00 pm at the Berlin-Brandenburg Academy of Sciences and Humanities in Berlin. A separate invitation will be sent to members of the media. Additional information about the 2017 prizewinners can be requested at the start of the new year by contacting the DFG Press and Public Relations Office or at http://www. . Detailed information about the Gottfried Wilhelm Leibniz Programme is available at: http://www.
News Article | September 9, 2016
During the process of cell division, chromosomes must be distributed equally between the two emerging daughter cells. One copy of each chromosome is created and remains glued to the original until threads, called microtubules, pull the chromosome pairs apart and distribute them to the two new cells. Researchers from the Max Planck Institute of Molecular Physiology in Dortmund and the Gene Center of the University of Munich (LMU) have now analyzed and modelled the structure of the point of attachment of the chromosomes to the threads, called the kinetochore. In the process, they have discovered how the different kinetochore proteins work together to bind the chromosomes securely to the microtubules. Cell division is vital for the continuation of life. If something goes wrong in, say, the distribution of chromosomes, abnormalities or serious diseases such as cancer may result. This is why scientists are keen to get to grips with the details of this fundamentally important process. "What I cannot create, I do not understand." This quote from physicist Richard Feynman is a guiding principle for Andrea Musacchio, Director at the Max Planck Institute and head of the study. He uses it to make a virtue of necessity, as the interplay of the individual components of the kinetochore during cell division in real cells does easily not lend itself to examination. "Only by taking the system apart and simplifying it do we have a chance of understanding how the kinetochore works - so we modelled it in the lab", explains Musacchio. The nuclear complex of a kinetochore contains about 30 proteins, making synthesis in the laboratory very difficult – like a construction kit with Lego blocks that all have different shapes and functions. But it gets worse: "Unlike Lego, these protein building blocks in the kinetochore interact with each other – but we didn't know how. Besides, you can't just walk into a store and pick the blocks you need off the shelf", reports John Weir, lead author of the study. The scientists began to synthesize the various building blocks of the kinetochore individually and eventually managed to construct an artificial kinetochore with 21 parts, which can connect chromosomes to microtubules. The whole system is far more complex in the natural world, as even more proteins have roles to play in real cells. Using the model, the scientists were able to examine the details of kinetochore function and structure. They found that the seven subunits of the protein complex CHIKMLN interact with each other. "This increases their binding strength with certain partners", explains Alex Faesen, who participated in the study. CHIKMLN is connected to the chromosome by a protein and binds to a ten-unit assembly (the KMN network), which is responsible for microtubule contact. "The whole structure consists of 21 subunits that form a bridge between the chromosome and the microtubules", says Kerstin Klare, another member of the research team, in summary. By modelling the kinetochore, the team has laid the foundation for further studies into the complex architecture and functionality of this vital structure. Their goal: to create an artificial model of cell division as a whole. "Because only when we can recreate these processes and cell components will we be in a position to truly understand how they work", says Musacchio. Explore further: Two unsuspected proteins may hold the key to creating artificial chromosomes More information: John R. Weir et al. Insights from biochemical reconstitution into the architecture of human kinetochores, Nature (2016). DOI: 10.1038/nature19333
News Article | November 15, 2016
Translation of the genetic code in proteins is a central process in life and takes place in the ribosome, a giant molecule consisting of two subunits. This is where long chains of amino acids are formed like on an assembly line. An interdisciplinary research group from Goethe University Frankfurt, the EMBL in Heidelberg, and the Gene Center of the University of Munich (LMU) has now succeeded in solving the structure of a central player in this process bound to the small ribosomal subunit: the protein containing a unique iron-sulphur domain with the nickname "Iron Hammer" splits the two subunits of the ribosome when a protein chain is completed so that production of a new protein can begin. The two subunits of the ribosome have to be actively split once the protein chain is complete otherwise errors occur in mRNA translation: research ignored this fact for a long time. Central player in this "ribosome recycling" process is the essential and highly dynamic metalloenzyme ABCE1. The iron-sulphur domain of ABCE1, known as the "Iron Hammer," rotates and presses the ribosomal subunits apart like a lever. To uncover this, the research group led by Professor Robert Tampé at the Institute of Biochemistry at Goethe University Frankfurt isolated a complex of the small ribosomal subunit with ABCE1 (post-splitting complex) by means of an innovative preparation method. This complex was chemically fixed and cut into pieces, while the original distance information was preserved. At the EMBL in Heidelberg, the researchers used highly advanced mass spectrometry to analyse these small fragments and relate them to each other revealing their original distances on nanometre scale. The group in Munich then examined the reconstructed complex with a high-resolution cryogenic electron microscope and was able to reconstruct a 3D model of the post-splitting complex with tightly bound ABCE1 from a vast collection of single-particle images. Professor Robert Tampé summarizes the significance of these results: "We have forced the rebellious and aggressive multi-domain enzyme ABCE1 into a new, unexpected state on the ribosome and used the combined expertise of three institutes to enrich textbook knowledge for coming generations of students."
News Article | November 15, 2016
Translation of the genetic code in proteins is a central process in life and takes place in the ribosome, a giant molecule consisting of two subunits. This is where long chains of amino acids are formed like on an assembly line. An interdisciplinary research group from Goethe University Frankfurt, the EMBL in Heidelberg, and the Gene Center of the University of Munich (LMU) has now succeeded in solving the structure of a central player in this process bound to the small ribosomal subunit: the protein containing a unique iron-sulphur domain with the nickname "Iron Hammer" splits the two subunits of the ribosome when a protein chain is completed so that production of a new protein can begin. The two subunits of the ribosome have to be actively split once the protein chain is complete otherwise errors occur in mRNA translation: research ignored this fact for a long time. Central player in this "ribosome recycling" process is the essential and highly dynamic metalloenzyme ABCE1. The iron-sulphur domain of ABCE1, known as the "Iron Hammer", rotates and presses the ribosomal subunits apart like a lever. To uncover this, the research group led by Professor Robert Tampé at the Institute of Biochemistry at Goethe University Frankfurt isolated a complex of the small ribosomal subunit with ABCE1 (post-splitting complex) by means of an innovative preparation method. This complex was chemically fixed and cut into pieces, while the original distance information was preserved. At the EMBL in Heidelberg, the researchers used highly advanced mass spectrometry to analyse these small fragments and relate them to each other revealing their original distances on nanometre scale. The group in Munich then examined the reconstructed complex with a high-resolution cryogenic electron microscope and was able to reconstruct a 3D model of the post-splitting complex with tightly bound ABCE1 from a vast collection of single-particle images. Professor Robert Tampé summarizes the significance of these results: "We have forced the rebellious and aggressive multi-domain enzyme ABCE1 into a new, unexpected state on the ribosome and used the combined expertise of three institutes to enrich textbook knowledge for coming generations of students." Explore further: Biochemists gain new insights into biogenesis of ribosomes More information: Kristin Kiosze-Becker et al, Structure of the ribosome post-recycling complex probed by chemical cross-linking and mass spectrometry, Nature Communications (2016). DOI: 10.1038/NCOMMS13248
Krokidis M.G.,University of Patras |
Marquez V.,Gene Center |
Marquez V.,Ludwig Maximilians University of Munich |
Wilson D.N.,Gene Center |
And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014
Ketolides, the third generation of expanded-spectrum macrolides, have in the last years become a successful weapon in the endless war against macrolide-resistant pathogens. Ketolides are semisynthetic derivatives of the naturally produced macrolide erythromycin, displaying not only improved activity against some erythromycin-resistant strains but also increased bactericidal activity as well as inhibitory effects at lower drug concentrations. In this study, we present a series of novel ketolides carrying alkyl-aryl side chains at the C-6 position of the lactone ring and, additionally, one or two fluorine atoms attached either directly to the lactone ring at the C-2 position or indirectly via the C-13 position. According to our genetic and biochemical studies, these novel ketolides occupy the known macrolide binding site at the entrance of the ribosomal tunnel and exhibit lower MIC values against wild-type or mutant strains than erythromycin. In most cases, the ketolides display activities comparable to or better than the clinically used ketolide telithromycin. Chemical protection experiments using Escherichia coli ribosomes bearing U2609C or U754A mutations in 23S rRNA suggest that the alkylaryl side chain establishes an interaction with the U2609-A752 base pair, analogous to that observed with telithromycin but unlike the interactions formed by cethromycin. These findings reemphasize the versatility of the alkyl-aryl side chains with respect to species specificity, which will be important for future design of improved antimicrobial agents. © 2014, American Society for Microbiology. All Rights Reserved.
Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology |
Frohlich T.,Gene Center |
Arnold G.J.,Gene Center |
Muller U.,Human Biology and BioImaging |
And 3 more authors.
Experimental Cell Research | Year: 2015
Lipid metabolism depends on lipid droplets (LD), cytoplasmic structures surrounded by a protein-rich phospholipid monolayer. Although lipid synthesis is the hallmark of sebaceous gland cell differentiation, the LD-associated proteins of sebocytes have not been evaluated systematically.The LD fraction of SZ95 sebocytes was collected by density gradient centrifugation and associated proteins were analyzed by nanoliquid chromatography/tandem mass spectrometry. 54 proteins were significantly enriched in LD fractions, and 6 of them have not been detected previously in LDs. LD fractions contained high levels of typical LD-associated proteins as PLIN2/PLIN3, and most proteins belonged to functional categories characteristic for LD-associated proteins, indicating a reliable dataset. After confirming expression of transcripts encoding the six previously unidentified proteins by qRT-PCR in SZ95 sebocytes and in another sebocyte line (SebE6E7), we focused on two of these proteins, ALDH1A3 and EPHX4. While EPHX4 was localized almost exclusively on the surface of LDs, ALDH1A3 showed a more widespread localization that included additional cytoplasmic structures. siRNA-mediated downregulation revealed that depletion of EPHX4 increases LD size and sebaceous lipogenesis. Further studies on the roles of these proteins in sebocyte physiology and sebaceous lipogenesis may indicate novel strategies for the therapy of sebaceous gland-associated diseases such as acne. © 2014 Elsevier Inc.
Herbach N.,Institute of Veterinary Pathology |
Bergmayr M.,Institute of Veterinary Pathology |
Goke B.,Ludwig Maximilians University of Munich |
Wolf E.,Gene Center |
Wanke R.,Institute of Veterinary Pathology
PLoS ONE | Year: 2011
The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPR dn transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPR dn transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPR dn transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPR dn transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPR dn transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPR dn transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis. © 2011 Herbach et al.
News Article | December 8, 2015
Viruses essentially consist of a protein coat that encapsulates the viral genetic material – usually one or more molecules of RNA. During an infection, the only viral component that actually gets into the host cell is the RNA (the coat protein is stripped off). But vertebrates like ourselves have an innate immune system that can detect viral intruders and initiate appropriate countermeasures. An immune sensor called RIG-I (the protein encoded by retinoic acid-inducible gene I) recognizes the foreign RNA and activates an immune reaction against the virus. But since host cells are themselves full of RNAs that are essential for their survival the identification of exotic viral RNA is no easy task. "We had already shown that the process is based on the recognition of two specific structural features of viral RNAs, as Professor Karl-Peter Hopfner (LMU Gene Center) explains. "But this finding alone did not fully explain exactly how RIG-I discriminates viral from cellular RNA," he adds. Now Hopfner and his research team have shown that RIG-I must be actively removed from cellular RNA in order to prevent it from triggering false alarms. The new findings appear in the online journal eLife. RIG-I distinguishes viral RNAs from cellular RNAs on the basis of their structural peculiarities. Once viral RNA is detected in the cell, a signal cascade is triggered which ultimately leads to the synthesis of antiviral proteins. "Interestingly, RIG-I is an protein that can hydrolyze ATP, the currency unit of metabolic energy in the cell, thus releasing the chemical energy stored in the compound," says Hopfner. "We have previously shown that RIG-I makes use of this energy to propel itself along the double-stranded RNA like a train on a railway track. But how this activity is linked to the recognition of viral RNA remained a mystery." The breakthrough came with the recent discovery of a mutation in RIG-I, which deprives the protein of its ability to hydrolyze bound ATP. This mutation turns out to be the underlying cause of Singleton-Merten Syndrome, a rare form of autoimmune disease characterized by tooth loss, bone demineralization and calcification of the vasculature. Hopfner's team has now shown that the mutant form of RIG-I is also unable to tell the difference between friend and foe, such that the RIG-I-dependent signal relay is activated by cellular, as well as viral, RNA molecules. "So we took a closer look at the set of cellular RNAs that interact with the mutated form of RIG-I," Hopfner continues. And to everyone's surprise, we found that the mutant RIG-I localizes to the ribosomes, which serve as the cell's protein factories. Ribosomes are made up of proteins and RNAs, and the mutant RIG-I binds predominantly to a double-stranded stretch of RNA that extends from the ribosomal surface. With the help of Hopfner's colleague Prof. Roland Beckmann and his team, RIG-I could be located on a Ribosomal RNA element by using cryo electron microscopy. "We concluded from this finding that RIG-I must hydrolyze ATP in order to detach itself from cellular RNA. If this mechanism is defective, RIG-I binds to double-stranded regions in cellular RNAs – in particular to those associated with the ribosomes – and the continuing activation of the signal cascade precipitates an autoimmune reaction. This discovery could contribute to the development of new therapeutic possibilities in the future," Hopfner says. Explore further: Team learns how cellular protein detects viruses and sparks immune response More information: Charlotte Lässig et al. ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA, eLife (2015). DOI: 10.7554/eLife.10859