Former Research Groups
Since the founding of the Rudolf Virchow Center former group leadershave received numerous offers of highly competitive positions elsewhere. They have been able to successfully pursue their scientific careers with W2 or W3 professorships at various universities. Since such changes require a certain amount of time, several members of these groups are still at the Center and can be reached through the list of staff. The former groups will also be important cooperation partners in the future.
Membrane Biophysics
The mechanism of protein transport through membranes is very complicated. Examples for protein transport are the Sec-systems of prokaryotic and eukaryotic cells or the Tom- and Tim-mediated protein imports into mitochondria. These systems require many different components and also metabolic energy in the form of ATP or membrane potential. In contrast to these multi-component systems, the translocation of prokaryotic toxins into eukaryotic target cells is a rather simple process that requires only one or two proteins and no energy. Very often the transport process of toxins into target cells is combined with the formation of ion channels in the cytoplasmic membrane.
Channel formation is achieved either by the toxin molecule itself, i.e. it contains the transport function as part of its primary sequence or the transport function is secreted separately in the supernatant of the prokaryotic cells.
Examples of the latter systems are the A-B toxins of Clostridium botulinum C2-toxin and Clostridium perfringens iota toxin. The A-components of these toxins possess ADP-ribosyltransferase activity inside the eukaryotic target cells after having entered them via the binding component B. A similar system is produced by Bacillus anthracis. In this case the toxic activity is caused by a receptor binding moiety called protective antigen (PA) and two enzymatically active components, edema factor (EF; a calcium and calmodulin-dependent adenylate-cyclase) and lethal factor (LF; a highly specific zinc metalloprotease). PA binds to cells, coordinates self-assembly of the complexes and finally delivers EF and LF to the cytosol of the target cell.
The processes involved in toxin transport across artificial lipid bilayers and cell cultures are the topics of our research, together with studying membrane active molecules with artificial lipid bilayer membranes.
Contact Data
Prof. Dr. Dr. h.c. mult. Roland Benz
was a Senior Professor at the Rudolf Virchow Center until 2013
Prof. Dr. Roland Benz
Professor of Biotechnology (Wisdom Professor)
School of Engineering and Science
Jacobs-University
Campus Ring 1
28759 Bremen
Mailing Adress:
P.O. Box 750 561
28725 Bremen
Tel. 0421 - 200-3151
Fax 0421 - 200-3249
e-mail: r.benz@jacobs-university.de
Structural Investigation of Protein Synthesis
We are interested in visualizing the protein synthesis machinery, particularly ribosomes at the atomic/molecular level. Ribosomes, composed of both proteins and RNA, are very important; first they make all the proteins required in a cell or organism. Secondly, they are also targets for several antibiotics. Ribosomes from bacteria and higher organisms differ significantly in their structure. These differences in structure allow some antibiotics to target only bacteria by inhibiting their ribosomes, while leaving human ribosomes unaffected.
A better understanding of their mechanism would be beneficial for the basic research and the fight against disease causing bacteria. We use Cryo-electron microscopy (Cryo-EM) as the main tool to determine the structure of various functional states of translating ribosomes.
Contact Data
Dr. Shashi Bhushan
since 2013 Assistant Professor at Singapore´s Science and Technology University
E-Mail: SBHUSHAN@ntu.edu.sg
more information: Singapore´s Science and Technology University
Molecular Virology
Human Cytomegalovirus (HCMV) is an important human pathogen that generally causes mild infections in healthy individuals. However, the virus can cause severe disease in immunocompromised patients and is the leading infectious cause of congenital damage in newborns. Since cytomegaloviruses are highly species-specific, HCMV cannot be studied in laboratory animals – instead, the mouse cytomegalovirus (MCMV) is used as a model. We investigate how the virus manipulates the host cell to its own advantage, and which genes and proteins are involved.
Contact
Professor Dr. Wolfram Brune
Heinrich Pette Institut
Leibniz Institut für Experimentelle Virologie
Martinistrasse 52 - 20251 Hamburg
Tel: +49-(0)-40-48051 351, Fax: -352
Email: wolfram.brune@hpi.uni-hamburg.de
Cardiac Target Proteins
Heart failure is one of the leading causes of death in the Western World. Despite modern drug therapies, the 5-year survival rate of patients diagnosed with heart failure still is only about 50%, and thus similar to malignant cancer. Therefore, there is an urgent need for new therapeutic strategies. Our work aims to identify mechanisms underlying the development of the disease. We focus on molecular mechanisms leading to pathological growth of cardiac myocytes, an early step in the pathogenesis of heart failure. We are studying a variety of potential target molecules that either inhibit or promote growth of cardiac myocytes. A second major focus is the regulation of fibroblast proliferation in the cardiac muscle. In failing hearts cardiac fibroblast proliferation results in extensive fibrosis of the tissue, both impairing the mechanical properties of the heart and contributing to dangerous arrhythmias. We perform studies in vivo in transgenic animals, with human tissue, in cell culture and in vitro to unravel the mechanism of action of these proteins.
Contact Data
Prof. Dr. Stefan Engelhardt
since October 2008 Director of the Institute of Pharmakology und Toxikology, Technische Universität München
E-Mail: pharma@ipt.med.tum.de
Weitere Informationen: www.ipt.med.tum.de
RNA Metabolism and Neuronal Diseases
The generation of mature mRNAs and their translation into proteins depends on the elaborate interplay of a large number of trans-acting factors in eukaryotes. These factors are often organized in functional units (called macromolecular machines), which catalyze the sequential steps in mRNA metabolism and coordinate their timing.
Using a combination of biochemistry, cell biology and structural biology (single particle cryo-electron microscopy and X-ray crystallography) our group studies the functional dynamics of key complexes acting on mRNA. These include the spliceosome, which removes non-coding sequences (introns) from pre-mRNA molecules, the SMN-complex, which assembles subunits of the spliceosome, as well as the ribosome, which translates the genetic information into proteins.
In addition, our group is interested in the question of how defects in mRNA metabolism can lead to human diseases. To this end, we analyze the etiology of the eye disease Retinitis pigmentosa and the neuromuscular disorder Spinal Muscular Atrophy.
Contact Data
Prof. Dr. Utz Fischer
till 2014 Group-Leader at the Rudolf Virchow Center.
Theodor-Boveri-Institut für Biowissenschaften
Biochemie
Am Hubland
D - 97074 Würzburg
Tel.: +49 931 31-84029
Fax: +49 931 31-84026
E-Mail: utz.fischer@biozentrum.uni-wuerzburg.de
Weitere Informationen: www.biozentrum.uni-wuerzburg.de/biochem
Molecular Cell Dynamics
The movement of cells in tissues and organs is prerequisite for many biological processes, for example wound healing, immune function, and cancer metastasis. The Molecular Cell Dynamics Laboratory has set up different live-cell microscopy systems in vitro and in vivo to investigate cellular and molecular migration mechanisms of immune cells (T lymphocytes, dendritic cells), stromal cells (fibroblasts, endothelial cells), as well as cancer cells. Some key proteins of interest are adhesion receptors (integrins, surface glycosaminoglycans), proteolytic enzymes (matrix metalloproteinases) as well as signaling pathways (Ras/Raf-mediated signals) which control cell migration and cell-cell communication. Understanding cell-matrix interactions in different cell types and extracellular matrices (collagen, fibrin) is also important for developing tissue engineering approaches to reconstruct chronic tissue defects, such as dermal ulcers.
To study such processes in vivo a multiphoton microscope was installed at the Rudolf Virchow Center in December 2004. Together with the Bielefeld Company "La Vision Biotec" we developed this microscope especially for such applications.
Contact Data
Prof. Dr. med. Peter Friedl
since Oktober 2007 Full Professor for Immune Regulation at the Nijmegen Centre for Molecular Life Sciences.
E-Mail: P.Friedl@ncmls.ru.nl
Weitere Informationen: http://www.rimls.nl/people/f/friedl/
HAD Phosphatases
HAD-type phosphatases are an emerging class of enzymes with essential functions for transcription, cellular metabolism and cytoskeletal dynamics. We aim to understand the regulation as well as the physiological and pathological roles of Chronophin and AUM, two novel mammalian HAD phosphatases that we have discovered. Building on the important role of Chronophin for cofilin-dependent actin remodeling, our research has a strong focus on signaling to the cytoskeleton. Altered cytoskeletal dynamics play crucial roles in the pathogenesis of cardiovascular diseases and malignant tumors, and we now know that Chronophin and AUM are deregulated in some of these diseases.
For this reason, we study the role of Chronophin and AUM in cell proliferation, adhesion and migration using various biochemical and cell biological methods. We also investigate the consequences of Chronophin- and AUM-inactivation in vivo using conditional mouse models that we have generated.
Contact Data
Prof. Dr. Antje Gohla
Professur für Biochemische Pharmakologie
am Lehrstuhl für Pharmakologie (Leiterin)
Universität Würzburg
Versbacher Str. 9
97078 Würzburg, Germany
Tel.: +49 931 31-80099
Fax: +49 931 31-48539
E-Mail: antje.gohla@uni-wuerzburg.de
Staff
Prof. Dr. Antje Gohla
Versbacher Str. 9
Kerstin Hadamek
Versbacher Str. 9
Angelika Keller
Versbacher Str. 9
Molecular Microscopy
Spectroscopic methods for detecting and analyzing individual molecules have become increasingly attractive and popular in biochemistry and biophysics over the past decade. Furthermore, an increasing number of scientific questions in molecular and cell biology are now being answered by examining individual bio-molecules, e.g. proteins and nucleic acids and their function. The advantage of these procedures is on the one hand the possibility of removing those molecules that overlay and mask the genuine dynamic signal of active molecules. On the other hand their concentration has to remain at the endogenous level of expression in biological systems to make it possible to resolve individual molecules.
Our goal is to observe single bio-molecules in living systems, perform intracellular analysis, and concomitantly to develop better pharmaceutical products. We want to continuously improve techniques of single molecule detection to increase the accuracy and extend the scope of application.
Contact Data
Dr. Gregory Harms
Faculty 9 Month
Wilkes University
Stark Learning Center
Tel.: +1-570-408-4828
E-Mail: gregory.harms@wilkes.edu
Architecture of Synapses
Signal transmission from a nerve cell to a recipient cell – for example a muscle cell – is mediated by special contact structures called synapses. Chemical mediators are secreted from a specialized nerve cell region called the “presynaptic active zone” and excite (or inhibit) the recipient cell via specific receptors on its surface.
The presynaptic active zone organizes the Ca2+-mediated release of neurotransmitters to activate neurotransmitter receptors localized at the postsynaptic membrane. How these synaptic compartments assemble and control their function is being intensively investigated. Genetic analysis in the fruit fly Drosophila allowed us to identify a master organizer of presynaptic active zones, a protein we called Bruchpilot. At synapses lacking Bruchpilot, clustering of presynaptic Ca2+-channels is defective, and efficiency of neurotransmitter release is dramatically reduced.
We are now investigating the architecture of active zones by systematically analyzing synapses in two model organisms, flies and mice. To this end, we combine genetic and biochemical analyses with a recent advance in light microscopy, i.e. stimulated emission microscopy (STED). STED greatly increases the resolution of fluorescence microscopy, revealing so far unseen substructures in the molecular architecture of synapses. Our results are relevant in the context of learning and memory as well as degenerative diseases of the nervous system.
Contact Data
Prof. Dr. Manfred Heckmann
Until 2011 Prof. Dr. Manfred Heckmann was involved with a project in the Bio-Imaging Center.
Physiologie II/Schwerpunkt Neurophysiologie
Röntgenring 9
D - 97070 Würzburg
Tel.: +49 931 31-82730
E-Mail: heckmann@uni-wuerzburg.de
Weitere Informationen: www.physiologie.uni-wuerzburg.de/neurophysiologie
Inflammatory Cytokine Signaling
Dysregulated cytokine signaling is involved in the pathogenesis of a large number of diseases including chronic inflammation (atherosclerosis, rheumatoid arthritis, Crohn’s disease, and multiple sclerosis), autoimmunity (type I diabetes), and cancer. Therefore, understanding cytokine signaling specificity is essential to generate more specific therapeutic intervention methods and avoid harmful side effects.
Cytokines are soluble immunomodulatory proteins secreted by a range of tissue and immune cells. Many cytokines transduce signals via shared cell surface receptors that form multi-molecular complexes comprising ligand-specific and signal transducing receptors. This explains why several signaling cascades are activated by a number of different cytokines, but poses the question as to how signaling specificity is achieved.
Using the family of interleukin-6-type cytokines as a model system our laboratory investigates the spatio-temporal resolution of cytokine receptor signaling and how this is affected by cross-talk mechanisms. Using classical protein biochemistry as well as advanced confocal microscopy we want to learn how intracellular trafficking of cytokine receptors affects signaling specificity and which molecular mechanisms are required to guide cytokine receptors to specific intracellular compartments. Genetic mouse models will help us to validate the physiological relevance of our findings.
Kontaktdaten
PD Dr. Heike Hermanns
till 2014 Junior Group Leader at the Rudolf Virchow Center, now Head of Hepatology Research Laboratory at the University Hospital Würzburg (Management: Prof. Dr. med. Andreas Geier; http://www.leberzentrum-wuerzburg.de/).
PD Dr. Heike Hermanns, AOR
University Hospital Würzburg
Department of Internal Medicine II
Head of Hepatology Research Laboratory
Auverahaus
Grombühlstr. 12
97080 Würzburg
Germany
Ph.: +49 (0)931 201 40030
Email: Hermanns_H@ukw.de
G-protein Coupled Receptors
In order to transduce a signal of a hormone or prescription drug across the plasma membrane G-protein-coupled receptors (GPCRs) need to undergo conformational changes. The focus of our research is to investigate such conformational changes during GPCR activation and deactivation. Therefore we develop FRET-based probes for GPCRs to image the conformational change in living cells and millisecond time resolution. The use of such FRET-based sensors allows us to study receptor ligand interaction directly at the level of the receptor itself. Thus we are able monitor the effects of potential future drugs at the protein level and can correlate the observed data with effects on different signalling pathways triggered by receptor activation.
Receptor interaction with β-arrestin is an important regulatory key element in the termination of G-protein-dependent receptor signalling. The interaction of a GPCR and β-arrestin is regulated by ligand binding and receptor phosphorylation by specific receptor kinases. Since β-arrestins not only turn off G-protein-dependent-signalling but represent starting points for novel signalling cascades, we are also interested to investigate receptor ligands which are able to discriminate between G-protein and β-arrestin mediated receptor signalling. Such compounds are called biased ligands and are of great value for basic research and hold the promise for fewer side effects for patient treatment.
Last but not least we are interested in the development of novel approaches to fluorescently label proteins. Of special interest are further developments of the tetracystein-biarsenical-tag technology with emphasis on the improvements of amino acid sequence motifs for labelling with FlAsH or ReAsH, as well as the development of novel colour variants of these small organic dyes.
Contact Data
Prof. Dr. Carsten Hoffmann
Rudolf-Virchow-Zentrum für Experimentelle Biomedizin
Universität Würzburg
Versbacher Str. 9
D - 97078 Würzburg
Tel.: +49 931 31-48304
Fax: +49 931 31-48539
E-Mail: c.hoffmann@toxi.uni-wuerzburg.de
Staff
Consuelo Alonso Canizal
Versbacher Str. 9
Prof. Dr. Carsten Hoffmann
Versbacher Str. 9
Cristina Perpina Viciano
Versbacher Str. 9
Dr. Benedikt Schmid
Versbacher Str. 9
Nicole Ziegler
Versbacher Str. 9
T Cell Surface Proteins
One of the main goals of immunology is to understand why autoimmune disorders occur. Ten years ago, studies into a lethal autoimmune disease in a mouse strain led to the discovery of a unique population of T lymphocytes that negatively regulate immune responses. These regulatory T cells (TReg cells or suppressor T cells) have since been confirmed to play an essential role in both self-tolerance and preventing exaggerated immune responses to foreign antigens.
However, significant gaps in our understanding of TReg cell biology remain, partly due to the lack of suitable markers for purifying these cells. All of the cell surface proteins that are currently used to identify TReg cells are also expressed on other T cell subsets. The most reliable marker of TReg cells is the transcription factor Foxp3, but as a nuclear protein it is unfortunately not a suitable marker for the purification and manipulation of viable TReg cells.
Our aim is to identify unique TReg cell surface markers through two approaches, namely by generating monoclonal antibodies against TReg cells and by comparing the membrane proteome of TReg cells with conventional T cells.
Contact Data
Prof. Dr. Thomas Hünig
Until 2008 Prof. Dr. Thomas Hünig was involved with a project in the RVZ Network.
Institut für Virologie und Immunbiologie
Versbacher Str. 7
D - 97078 Würzburg
Tel.: +49 931 201 - 49 951
E-Mail: huenig@vim.uni-wuerzburg.de
Membrane/Cytoskeleton Interactions
Streptococcus pneumoniae is a common pathogen causing the most frequent form of bacterial meningitis in adults and the second most common form in children. Pneumococcal meningitis leads to death in 30% of cases, and results in neurological damage in around one third of the survivors.
The major virulence factor of S. pneumoniae is the pore-forming toxin pneumolysin. It belongs to the family of cholesterol-dependent cytolysins, which include perfringolysin, streptolysin and others. Pneumolysin induces rapid cell lysis or apoptosis in a concentration-dependent manner. Despite the serious outcome and prognosis of pneumococcal meningitis, the cell death rate is relativly low.
Recently, we described cholesterol-dependent rapid activation of RhoA and Rac1 GTPases mediated by pneumolysin that resulted in actin cytoskeletal remodeling in neuronal cells (Iliev et al., PNAS, 2007). Our aim is to clarify the molecular steps leading to activation of small GTPases and subsequently redistribution of the cytoskeleton and changes in cell signaling of neuronal target cells after pneumolysin challenge. Various toxin mutants (e.g. non-pore forming) will be employed to analyze the role of macropore/micropore formation in GTPase activation and identify which toxin domains are involved. We will analyze how the small GTPases and their regulators (GEFs and GAPs) are recruited to the cell membrane cholesterol-rich microdomains and how they are distributed in the membrane or cytosol. Finally, we will investigate how the toxin alters dendritic spine (precursors of mature synapses) formation, which depends on small GTPases. These effects will be compared with other pore-forming toxins.
The results will help us to better understand the mode of action of the whole group of cholesterol-dependent cytolysins in host pathogen interactions, and define toxin-initiated neuronal damage, including identifying potential drug targets.
Contact Data
Dr. Asparouh Iliev
formerly leader of Emmy Noether-Fellow.
Institute of Anatomy
University of Bern
Baltzerstrasse 2, 3000 Bern 9
Switzerland
Tel. +41(0)31 631 3887
E-Mail: asparouh.iliev@ana.unibe.ch
Neutralizing cyclopeptides against cardiostimulatory ß1-adrenoceptor autoantibodies
Heart failure is one of the most frequent diseases and causes of death in Germany and other industrialized countries. Cardiac pump failure results in insufficient blood supply to the body. In addition to complex hormonal mechanism, recent clinical and experimental data point towards an important role of autoimmune processes in the pathophysiology of heart failure: In 15-30% of patients with heart failure, functionally active autoantibodies stimulating the beta1-adrenergic membrane receptor – which represents the key receptor in myocardial excitation/contraction coupling – appear to be causally involved in the induction and course of the disease.
In the rat we have recently demonstrated that stimulatory antibodies specifically targeting the second extracellular receptor-loop of the beta1-receptor (anti-beta1-ECII) may, in fact, cause cardiac dilatation and progressive pump failure. In this model, novel beta1-ECII-homologous cyclopeptides (beta1-ECII-CP), originally designed to neutralize circulating receptor-antibodies, not only prevented the antibody-induced development of cardiac dilatation and failure, but actually even reversed overt heart failure. After 4-5 injections, the cyclopeptides evoked a significant decrease in and finally cessation of anti-beta1-ECII antibody-production in spite of continued boosts with the immunogen. A GoBio grant supported our work on the development of novel cyclopeptide-based treatment strategies for heart failure. We are investigating in detail the cardioprotective and immunological effects of optimized cyclopeptide variants and mutants using different application strategies and also alternative heart failure (animal) models. These studies equally served to gain pre-clinical data in the aim to use receptor cyclo-peptides as a novel therapeutic approach in anti-beta1-ECII-positive heart failure patients.
In parallel, we developed a novel fluorescence-based screening strategy for the specific diagnostic detection of such stimulatory antibodies. For this purpose, we employed a new highly sensitive and specific fluorescent cAMP-sensor, which permits visualiziation and quantification of receptor-mediated increases in cellular cAMP by fluorescence resonance energy transfer (FRET). In this diagnostic assay, receptor-cyclopeptides are used to ascertain the specificity of anti-beta1-AR-mediated receptor activation. The developed diagnostic and therapeutic strategies and agents are protected by patents and served as a basis for founding the spin-off biotech company Corimmun GmbH.
Contact Data
Prof. Dr. med. Roland Jahns
Until 2012, Prof. Dr. med. Roland Jahns was involved with a project in the RVZ Network.
Leiter Interdisziplinäre Biomaterial- und Datenbank Würzburg (IBDW)
Universitätsklinikum Würzburg
Straubmühlweg 2A, Haus A9
D - 97078 Würzburg
Tel.: +49 931 201-46368
Fax: +49 931 201-646381
E-Mail: jahns_r@klinik.uni-wuerzburg.de
Weitere Informationen: http://www.ibdw.ukw.de/
Immune Cell Signaling
The primary function of the immune system is to recognize and eliminate pathogens. This task requires immune cells to be reactive to a wide range of antigens. While mechanisms are in place to prevent immune activation by innocuous antigens, including self-antigens, a significant percentage of the population develops autoimmune diseases.
Our laboratory seeks to understand the genetic polymorphisms that predispose individuals to autoimmunity and the regulatory pathways that fail during onset of disease. Our main approach is the genetic manipulation of model organisms by RNA interference (RNAi). We employ lentiviral transgenesis to generate animals with target genes constitutively silenced by RNAi. After pioneering this strategy in the most widely used model for type 1 diabetes, we are now refining lentiviral technology to make it more versatile and specific for studying of immune tolerance. Understanding genetic factors and functional pathways involved in autoimmunity should ultimately help develop new therapeutic approaches.
Contact Data
Dr. Stephan Kissler
since April 2012 at the Joslin Diabetes Center, Boston, USA
Joslin Diabetes Center
One Joslin Place
Boston, MA 02215
USA
Phone: +1-617-309-4071
E-Mail: stephan.kissler@joslin.harvard.edu
Receptor Signaling
Cyclic nucleotides – cyclic AMP (cAMP) and cyclic GMP (cGMP) – belong to the most ubiquitous intracellular messengers. The discovery of cAMP, cGMP and their signaling pathways in the 1950s and 1960s led to the concepts of second messengers and intracellular signaling. Both are produced in response to multiple stimuli, act on several intracellular targets, and regulate a vast array of biological functions.
However, in spite of the fundamental importance of these signaling systems, very little is known about the temporal and spatial patterns of their production and action. In fact, space and time seem to play almost no role in current concepts of intracellular signaling. To gain an insight into these dimensions, we develop methods to create images of these second messengers in intact cells, and to resolve these intracellular signals in space and in time.
Contact Data
Prof. Dr. Martin Lohse
Rudolf-Virchow-Zentrum für Experimentelle Biomedizin
Universität Würzburg
Versbacher Str. 9
D - 97078 Würzburg
Tel.: +49 931 201-48401
Fax: +49 931 201-48411
E-Mail: lohse@toxi.uni-wuerzburg.de
Staff
PD Dr. Davide Calebiro
Versbacher Str. 9
Monika Frank
Versbacher Str. 9
Prof. Dr. Martin Lohse
Versbacher Str. 9
Understanding and targeting ubiquitination and phosphorylation networks
Cells have evolved a staggering range of mechanisms to regulate the abundance, localization, conformation, and activity of proteins in response to biological stimuli. These mechanisms are typically driven by posttranslational protein modifications. Sonja Lorenz’ lab aims to unravel the structural basis and functional consequences of posttranslational modifications with a particular focus on the ubiquitin system in tumorigenesis and infection. To this end the lab combines high-resolution structural techniques (cryo-electron microscopy, X-ray crystallography, NMR spectroscopy) with biophysical, biochemical, and cell biological techniques.
The ubiquitin system regulates countless physiological and disease-associated processes and has emerged as a powerful arena for therapeutic efforts. Ubiquitination is mediated by a cascade of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and ubiquitin ligases (E3), counteracted by deubiquitinases. E3s have pivotal roles in determining the specificity of ubiquitin signaling by recruiting specific substrates for modification and defining which types of ubiquitin modifications they are decorated with, thus triggering particular signaling responses. With an estimated 1000 members in the human proteome, the E3 family is the most diversified among the different classes of ubiquitination enzymes and provides particularly interesting targets for therapeutic interference.The immense potential of modulating the activities of E3 enzymes for therapeutic benefit has become evident from the finding that the clinical efficacy of thalidomide in the treatment of hematological malignancies originates from its interaction with a particular RING-type E3, CRL4CRBN. This milestone discovery has given rise to several immunomodulatory drugs and refueled the development of proteolysis-targeting chimeras (PROTACs) that harness the activities of RING-type E3 enzymes to mark pathogenic proteins for degradation. In contrast, the development of small-molecule probes targeting HECT-type E3 enzymes is still in its infancy – despite the presence of a potentially ‘druggable’ active site in these ligases and their clear pathophysiological significance.
The Lorenz lab investigates the macromolecular complexes, conformational dynamics, and functions of HECT-type ubiquitin ligases to understand the mechanisms underlying their substrate specificity, linkage specificity, regulation, and vulnerability to small-molecule inhibitors. A major focus is on ligases crucial in tumorigenesis, e.g. HUWE1. A second line of research elucidates the crosstalk of ubiquitination and phosphorylation in infectious disease. Work in the Lorenz lab is supported by the DFG Emmy Noether Program, GRK 2243 (“Understanding ubiquitylation: from molecular mechanism to disease”), FOR 2314 (“Targeting therapeutic windows in essential cellular processes for tumor therapy”), and the Mildred Scheel Cancer Center (Deutsche Krebshilfe). In 2018 Sonja Lorenz was named an EMBO Young Investigator.
Contact Data
Dr. Sonja Lorenz
independent group leader at the Max Planck Institute for Biophysical Chemistry, Göttingen, since March 2021
Email: Sonja.lorenz@mpibpc.mpg.de
further information:
https://www.mpibpc.mpg.de/lorenz
Ligand-Receptor Recognition
Analysis of the human genome has clearly shown that the complexity of an organism is more than just the sum of its genes. It is therefore necessary to understand how signaling diversity is achieved with a relatively small number of genes. One important aspect in this investigation is to analyze how biomolecules interact with each other. In the past, protein-protein interactions were interpreted strictly via a key-and-lock mechanism. New data however reveal that proteins often interact with more than one binding partner. This defined specificity might not only be useful to enhance redundancy in important signaling cascades, but it could also enhance signaling diversity.
Using structural biology as a tool we are studying two protein families of secreted factors: the cytokines IL-4, -5 and -13, which are involved in the development and progression of allergic diseases and asthma, and the bone morphogenetic proteins, which are important regulators in embryonal development as well as organ and tissue homeostasis. Both protein families represent prime examples of ligand-receptor promiscuity. Understanding how a ligand can interact with various different receptors will yield important insights into how proteins generate and modulate binding specificity at the molecular level.
Contact Data
Prof. Dr. Thomas Müller
Until 2008 Dr. Thomas Müller was involved with a project in the RVZ Network.
Julius-von-Sachs-Insitut für Biowissenschaften
Lehrstuhl für Botanik I - Pflanzenphysiologie und Biophysik
Julius-von-Sachs-Platz 2
D - 97082 Würzburg
Tel.: +49 931 31 - 89207
E-Mail: mueller@botanik.uni-wuerzburg.de
Weitere Informationen: https://www.biozentrum.uni-wuerzburg.de/bot1/forschung/prof-dr-thomas-mueller/
Posttranslational Gene Regulation
Whether an individual will become a male or a female depends on an embryological process called sex determination. During early development an undifferentiated gonad primordium forms that can develop into either a testis or an ovary. These organs in turn then produce the male or female hormones, which induce further differentiation typical for a male or female. The developmental decision is initiated by a hierarchically structured cascade of gene activities, called the sex determination cascade.
In humans and most mammals, one of the few genes on the Y chromosome, the SRY gene, is the master regulator at the top of this cascade. Its presence initiates male development. Disorders of sex determination have severe pathological consequences that range from organ malformations and mental disorders to partial or complete sex reversal.
In contrast to most other developmental processes, the regulatory network and molecular function of the components of the sex-determining cascade are not well understood. For all other developmental control processes the master regulatory genes are well conserved and the downstream components responsible for carrying out the often species-specific genetic program (the so-called phenotype) are variable. Intriguingly, for the sex determination cascade the situation is the other way round: Genes at the top of the cascade such as SRY are unstable in evolutionary terms, and can be lost and differ in various groups of organisms. In contrast, the downstream genes are conserved, even between flies, worms, and humans.
We want to contribute to a better understanding of the regulation and function of the sex determination cascade, and we are interested in understanding the evolutionary forces that generate the high variability in primary sex-determining mechanisms.
Contact Data
Prof. Dr. Manfred Schartl
Until 2009 Prof. Dr. Manfred Schartl was involved with a project in the RVZ Network.
Theodor-Boveri-Institut für Biowissenschaften
Physiologische Chemie I
Am Hubland
D - 97074 Würzburg
Tel.: +49 931 888 - 41 48
E-Mail: phch1@biozentrum.uni-wuerzburg.de
Weitere Informationen: www.pch1.biozentrum.uni-wuerzburg.de/
Inflammation and Tumor Biology
The migration of leukocytes (white blood cells) into tissues is a central process in the pathogenesis of inflammation, which can affect virtually any organ. We investigate the molecular mechanisms mediating tissue-specific recruitment of leukocytes in the pathogenesis of inflammation. Our focus is on the earliest steps, i.e. when leukocytes roll along the blood vessel wall, and their subsequent extravasation; and on the later steps, i. e. epithelial localization. We want to learn how adhesion molecules of the selectin and integrin families mediate these critical steps in the inflammatory cascade, what their molecular interactions with other membrane-bound and cytosolic proteins are, and how we can interfere with their functions to treat inflammatory disorders.
Contact Data
Prof. Dr. med. Michael P. Schön
since April 2008 Director of Department Dermatologie, Venereology and Allergology at the Universitätsmedizin Göttingen.
E-Mail: michael.schoen@med.uni-goettingen.de
Weitere Informationen: www.med.uni-goettingen.de/de/content/medversorgung/218_327.html
BMP Receptors - Structure and Function
Bone morphogenetic proteins (BMPs) and BMP-like proteins are key regulators of organ development and tissue regeneration. Dysregulation of BMP signaling can result in tumor formation, or cardiovascular, musculoskeletal and urogenital diseases. To understand how BMPs bind and activate their receptors and how they are regulated by extracellular modulator proteins, we are studying the structure of ligand receptor complexes and the energetics and kinetics of BMP interactions with receptors and modulator proteins. We are generating BMPs that mimic mutations in familial disorders and which have useful properties for applications in regenerative medicine and musculoskeletal diseases.
Contact Data
Prof. Dr. Walter Sebald
Until 2008 Prof. Dr. Walter Sebald was involved with a project in the RVZ Network.
Theodor-Boveri-Insitut für Biowissenschaften
Physiologische Chemie II
Am Hubland
D - 97074 Würzburg
Tel.: +49 931 888 - 41 11
E-Mail: sebald@biozentrum.uni-wuerzburg.de
Functional Proteomics
Recent advances in mass spectrometry have rendered it a key technology in proteome research, since it is able to efficiently detect minute quantities of peptides. This enables the identification of proteins derived from 2D-PAGE separation by comparing databases of mass spectrometric information. In combination with miniaturized high performance liquid chromatography (nano-HPLC) even complex peptide mixtures can be analyzed.
After completing many genome projects, ongoing proteome projects highlight the important role of protein modifications. Modifications such as phosphorylation and glycosylation are probably present on every second protein and play important roles in various biological and biochemical pathways, e.g. signal transduction and cell-cell recognition. In addition to long established gel based technologies, they can be identified using a number of strategies based on mass spectrometry and different HPLC methods.
Contact Data
Prof. Dr. Albert Sickmann
since September 2008 Director of the Department of Proteomics at the
Institute for Analytical Sciences (ISAS)
E-Mail: albert.sickmann@isas.de
Weitere Informationen: www.isas.de
Architecture of Synapses
Signal transmission from a nerve cell to a recipient cell – for example a muscle cell – is mediated by special contact structures called synapses. Chemical mediators are secreted from a specialized nerve cell region called the “presynaptic active zone” and excite (or inhibit) the recipient cell via specific receptors on its surface.
The presynaptic active zone organizes the Ca2+-mediated release of neurotransmitters to activate neurotransmitter receptors localized at the postsynaptic membrane. How these synaptic compartments assemble and control their function is being intensively investigated. Genetic analysis in the fruit fly Drosophila allowed us to identify a master organizer of presynaptic active zones, a protein we called Bruchpilot. At synapses lacking Bruchpilot, clustering of presynaptic Ca2+-channels is defective, and efficiency of neurotransmitter release is dramatically reduced.
We are now investigating the architecture of active zones by systematically analyzing synapses in two model organisms, flies and mice. To this end, we combine genetic and biochemical analyses with a recent advance in light microscopy, i.e. stimulated emission microscopy (STED). STED greatly increases the resolution of fluorescence microscopy, revealing so far unseen substructures in the molecular architecture of synapses. Our results are relevant in the context of learning and memory as well as degenerative diseases of the nervous system.
Contact Data
Prof. Dr. Stephan Sigrist
since September 2008 Professor at the Institute for Biology, Genetics, Freie Universität Berlin
E-Mail: stephan.sigrist@fu-berlin.de
Weitere Informationen: http://genetik.bcp.fu-berlin.de
Molecular Tumor Biology
Cancer is the second leading cause of death in Europe. It arises due to damage to the DNA, which most of the time can be repaired. However, when repair mechanisms occasionally fail, mutations can accumulate, eventually leading to out-of-control growth of abnormal cells. The most frequent mutations in cancer patients are found in the p53 tumor suppressor gene, which normally functions as a "guardian of the genome" to prevent the development of tumors. Recently two novel genes (p63 and p73) have been identified which share significant structural and functional homology with p53. Despite the striking similarities, however, their roles in tumorigenesis appear to be quite different. Our research therefore focuses on a comparative analysis of the three genes using genetic approaches in both cell culture and animal models. The goal of our research is to understand the functional roles of the individual p53 family members in normal development and cancer.
Contact Data
Prof. Dr. Thorsten Stiewe
since April 2007 Professor at the Institute for Molekular Biology and Tumor Research Universität Marburg
E-Mail: thorsten.stiewe@staff.uni-marburg.de
Weitere Informationen: www.imt.uni-marburg.de
Hormonal Regulation of Metabolism
Adaption to changes in nutrient availability is pivotal for survival of living organisms. Specific responses to fasting and feeding in different organs are regulated by a complex array of hormonal cues. Deregulation of nutrient sensing leads to development of metabolic diseases including type 2 diabetes (T2D). We combine genetic and biochemical approaches to understand the complex signaling events occurring in different organs (e.g. liver and adipose tissue) during fasting, feeding and other physiological conditions.
Adipose tissue and liver are central to the adaptation to both food deprivation and ingestion of food as they can store large quantities of nutrients and release them when needed. In the fed condition insulin stimulates storage of sugars and lipids in liver and triglycerides in adipose tissue. Upon fasting adipose tissue responds to shortage of nutrients by inducing lipolysis – a process leading to mobilization and release of free fatty acids (FFAs) and glycerol through catabolism of stored triglycerides. Liver catabolizes stored polysaccharides and induces gluconeogenesis (de novo glucose production) from glycerol and other substrates upon nutrient deprivation. Hepatic sugar absorption and utilization decreases, while beta-oxidation of adipose tissue-derived FFAs and production of ketone bodies is induced. Importantly, uncontrolled activation of the fasting response in these organs largely independent of changes in food supply contributes to chronic hyperglycemia and hyperlipidemia, hallmarks of T2D that constitutes a major world-wide health concern.
Recently, we discovered gut-derived serotonin (GDS) as a fundamentally new hormone implicated in regulation of the fasting response in mice. We showed that GDS promotes lipolysis in adipose tissue and gluconeogenesis in liver while it blocks hepatic glucose uptake. Strikingly, inhibition of GDS synthesis was sufficient to ameliorate hyperglycemia and hyperlipidemia in diabetic mice. However, molecular mechanisms mediating GDS action on adipose tissue and liver are unknown. Currently, one important task of our laboratory is to understand these mechanisms using a combination of targeted and unbiased approaches.
Additionally, we are focusing on identification of novel signaling cascades and hormonal cues in regulation of lipolysis in adipose tissue as well as glugoneogensis, FFAs β-oxidation and ketone bodies production in liver using both genetic and unbiased approaches. Our research group is supported by the Emmy Noether Program of the German Research Foundation.
In-Vivo-Imaging
In our laboratory we have shown that bacteria injected intravenously into live animals entered and replicated in solid tumors and metastases. We can visualize the tumor specific amplification process in real time using luciferase-catalyzed luminescence and GFP-flourescence, which revealed the location of the tumors and metastases. Attenuated strains of E. coli, Vibrio cholerae, Salmonella thyphimurium andListeria monocytogenes all entered and replicated in tumors.
Similarly, the cytosolic vaccinia virus also showed tumor specific entry and replication as shown by low light imaging. The colonization of tumors by microorganisms was also observed in immunocompetent and immunocompromised rodents with syngeneic and allogeneic tumors. The ability of small number blood-borne microorganism to escape the host’s immunosurveillance by finding sanctuary in the tumor tissues may allow the development of a tumor “finding” live vectors for simultaneous diagnosis and therapy of cancer in humans.
Contact Data
Prof. Dr. Aladar Szalay
Theodor-Boveri-Institut am Biozentrum
Universität Würzburg
Am Hubland
97074 Würzburg
Tel: +49 931 - 31 84010
Single molecule studies of DNA repair
DNA is damaged continuously by agents that occur naturally within our cells as well as by exogenous factors such as high-energy radiation. In addition to the diverse damage introduced into previously ”healthy” DNA, the replication process itself causes errors in the genetic code (for instance base-base mis-pairs). If unrepaired, such damage and errors in the DNA can lead to cell death or diseases such as cancers. To maintain genomic stability, a number of DNA repair mechanisms have evolved, such as base-excision repair (BER), nucleotide-excision repair (NER), recombinational repair, mismatch repair (MMR), and direct damage reversal. These DNA repair systems each target different types of DNA damage and many of them are evolutionary conserved.
We use atomic force microscopy (AFM) in combination with other biophysical and biochemical techniques to study protein-DNA complexes involved in DNA repair. AFM enables us to directly visualize molecular assemblies at the level of the individual molecules. We are particularly interested in understanding the different DNA damage recognition strategies developed by the various DNA repair mechanisms. A second focus in our laboratory is the advancement of AFM to allow access to increased information on the sample. In this context, we are developing a combined fluorescence-AFM system for high resolution imaging of multi-protein complexes.
Membrane Biology
Throughout life, cells communicate to coordinate the organism’s response to stimuli. Cells release extracellular vesicles that carry signals to alter development or disease response. Released vesicles can also seal the cell membrane after damage. The goal of our research is to discover how vesicles bud from the surface of cells, how cells take up extracellular vesicles, and what signals extracellular vesicles send in animals. Defining how vesicles form is an essential first step to designing strategies to induce or suppress their formation and thereby determine their signaling capability. This research could also lead to new strategies to monitor or influence disease severity.
Most cells release extracellular vesicles (EVs) carrying lipid, protein, and nucleic acid signals. While much is known about their signaling potential, EV formation is poorly understood. As a postdoctoral fellow, Dr. Wehman used the genetic model system C. elegans to discover the first protein that prevents EV budding, TAT-5. In tat-5 mutant worms, too many EVs are produced. TAT-5 is an evolutionarily conserved protein that regulates the distribution of specific lipids across the two layers of the plasma membrane. This finding suggests that lipids have instructive roles in regulating membrane dynamics. Our research aims to define exactly how TAT-5 and lipid distribution regulate EV budding.
In addition to TAT-5, conserved regulators of viral budding also have a role in EV budding in C. elegans, including the small GTPase RAB-11 and the membrane-sculpting complex known as ESCRT. Using the same strategy that identified TAT-5, RAB-11, and the ESCRT machinery, we are using the power of C. elegans genetics to identify additional proteins that regulate EV budding. Our studies are building a pathway of proteins that regulate TAT-5 localization and activity and thereby EV release. The proteins we identify may be used to alter EV production in other systems, which could impact the availability of non-invasive biomarkers and have the potential to influence disease state.
In addition to overproducing EVs, tat-5 mutant worms also have defects in EV uptake. Studying tat-5 and other mutants revealed that cells take up organelles released during cell division, including the mitotic midbody and the meiotic polar body. Thus, we can also use C. elegans to study the pathways of EV uptake and determine their fate. Analyzing defects in EV uptake complements our studies on EV budding and will allow us to elucidate the interplay of lipids and lipid regulators during dynamic remodeling of the membrane. Studying the fate of EVs also provides important insights into the mechanisms of EV signaling.
Finally, studying the mechanisms of EV production has provided us with techniques to induce or prevent their formation. This allows us to test which signaling pathways require EVs for signaling to occur. In flies and mice, EVs carry morphogens important for development. We are studying how changing EV production or uptake affects conserved signaling pathways during C. elegans development. In summary, our research will determine the roles of lipid and protein molecules during membrane dynamics and will define the intercellular signaling roles of EVs.
Immune Pathogenesis of Atherosclerosis
Atherosclerosis with its clinical manifestations, such as myocardial infarction, stroke and peripheral artery disease, is still the leading cause of death in the Western World. Inflammation has emerged as a crucial force driving atherosclerotic lesion formation. Initiated by the activation and dysfunction of endothelial cells, leukocyte subsets are recruited and accumulate in atherosclerotic lesions. Importantly, immune responses are described to participate in all phases of atherosclerosis and several pro-atherogenic and atheroprotective cytokines and cell populations have been defined. The exact functions of immune cells in controlling the development of atherosclerosis, however, remain elusive to date.
By targeting specific cytokines and key molecules (e.g. microRNAs) we address the role of different immune cell subpopulations in atherosclerosis. Given the remarkable role of adaptive and innate immunity in atherosclerosis, targeting of its cellular constituents and understanding the complex equilibrium and interplay between immune cell subpopulations that contribute to the process of atherosclerosis will be important to identify new therapeutic approaches for treating this disease.
Contact Data
Prof. Dr. Alma Zernecke-Madsen
Director of the Institute of Experimental Biomedicine, Chair II
Institute for Experimental Biomedicine
Chair II
House D16
Josef-Schneider-Str. 2
97080 Würzburg
Tel.: +49 931 201-48330
E-Mail: zernecke_a@ukw.de
