Max Planck Institute for Medical Research

www.mpimf-heidelberg.mpg.de
Heidelberg, Germany

The Max Planck Institute for Medical Research in Heidelberg, Germany, is a facility of the Max Planck Society for basic medical research. Since its foundation, six Nobel Prize laureates worked at the Institute: Otto Fritz Meyerhof , Richard Kuhn , Walther Bothe , André Michel Lwoff , Rudolf Mößbauer and Bert Sakmann . The Institute has close ties with Heidelberg University. Wikipedia.


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Urban G.,Max Planck Institute for Medical Research
Nature Methods | Year: 2017

Teravoxel volume electron microscopy data sets from neural tissue can now be acquired in weeks, but data analysis requires years of manual labor. We developed the SyConn framework, which uses deep convolutional neural networks and random forest classifiers to infer a richly annotated synaptic connectivity matrix from manual neurite skeleton reconstructions by automatically identifying mitochondria, synapses and their types, axons, dendrites, spines, myelin, somata and cell types. We tested our approach on serial block-face electron microscopy data sets from zebrafish, mouse and zebra finch, and computed the synaptic wiring of songbird basal ganglia. We found that, for example, basal-ganglia cell types with high firing rates in vivo had higher densities of mitochondria and vesicles and that synapse sizes and quantities scaled systematically, depending on the innervated postsynaptic cell types. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


News Article | May 16, 2017
Site: phys.org

Using hydrogel, a gel with a gradient that can be used to mimic the stiffness of human body tissues, the researchers were able to generate positive outcomes for the growth of stem cells. Dr Yu Suk Choi from UWA's School of Human Sciences at The University of Western Australia led the international collaboration which also included researchers from the University of California, San Diego (USA) and Max Planck Institute for Medical Research (Germany). "Stem cells work by using the 'stiffness' of surrounding tissue as a gauge to identify the way they need to behave in a particular environment in the human body," Dr Choi said. "By using hydrogel to mimic the stiffness of tissue, we found we could 'trick' the stem cells into behaving in particular ways to help them grow and encourage the cells to behave in positive, regenerative ways. "Hydrogel is simple and inexpensive to produce and could have a wide range of applications in biology labs that don't always have the infrastructure available to use other methods to mimic the stiffness of tissue to aid stem cell growth." Dr Choi said the research may have important uses in combating serious illnesses affecting the human population. "Many degenerative diseases result in changes to tissue stiffness which alters the behavior of cells," he said. "But by controlling tissue stiffness we can revert cell behavior back to normal, and change their behavior at the disease site into more regenerative behaviour. This will help us us to treat diseases such as cancer that are currently very difficult to treat." The next step for the researchers will be to use hydrogel with patient originated cells to further understand the effect of tissue stiffness on cell behaviour. More information: William J. Hadden et al. Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1618239114


Benjdia A.,Max Planck Institute for Medical Research
Current Opinion in Structural Biology | Year: 2012

Light is essential for many critical biological processes including vision, circadian rhythms, photosynthesis and DNA repair. DNA photolyases use light energy and a fully reduced flavin cofactor to repair the major UV-induced DNA damages, the cis-syn cyclobutane pyrimidine dimers (CPDs) and the pyrimidine-pyrimidone (6-4) photoproducts. Catalysis involves two photoreactions, the photoactivation which leads to the conversion of the flavin cofactor to its catalytic active form and the photorepair whose efficiency depends on a light-harvesting antenna chromophore. Very interestingly, an alternative and light-independent direct reversal mechanism to repair a distinct photolesion is found in bacterial spores, catalyzed by spore photoproduct lyase. This radical SAM enzyme uses an iron-sulfur cluster and S-adenosyl- l-methionine (SAM) to split a specific photoproduct, the so-called spore photoproduct (SP), back to two thymidine residues. The recently solved crystal structure of SP lyase provides new insights into this unique DNA repair mechanism and allows a detailed comparison with DNA photolyases. Similarities as well as divergences between DNA photolyases and SP lyase are highlighted in this review. © 2012 Elsevier Ltd.


Dominguez R.,University of Pennsylvania | Holmes K.C.,Max Planck Institute for Medical Research
Annual Review of Biophysics | Year: 2011

Actin is the most abundant protein in most eukaryotic cells. It is highly conserved and participates in more protein-protein interactions than any known protein. These properties, along with its ability to transition between monomeric (G-actin) and filamentous (F-actin) states under the control of nucleotide hydrolysis, ions, and a large number of actin-binding proteins, make actin a critical player in many cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to the regulation of transcription. Moreover, the interaction of filamentous actin with myosin forms the basis of muscle contraction. Owing to its central role in the cell, the actin cytoskeleton is also disrupted or taken over by numerous pathogens. Here we review structures of G-actin and F-actin and discuss some of the interactions that control the polymerization and disassembly of actin. © 2011 by Annual Reviews. All rights reserved.


Benz J.,Max Planck Institute for Medical Research | Meinhart A.,Max Planck Institute for Medical Research
Current Opinion in Microbiology | Year: 2014

Bacteria do not live anchoretic; rather they are constantly in touch with their eukaryotic hosts and with other bacteria sharing their habitat. Therefore, bacteria have evolved sophisticated proteinaceous weapons. To harm other bacteria, they produce antibacterial effector proteins, which they either release into the environment or export via direct intercellular contact. Contact-dependent killing is mediated by two specialized secretion systems, the type V and VI secretion system, whereas contact-independent processes hijack other transport mechanisms. Regardless of the transport system, cells co-express immunity proteins to protect themselves from suicide and fratricide. In general, effector protein activities and secretion mechanisms differ between Gram-positive and Gram-negative bacteria and evidence is emerging that different effector/immunity systems act synergistically and thus extend the bacterial armory. © 2013 The Authors.


Foucar L.,Max Planck Institute for Medical Research
Journal of Applied Crystallography | Year: 2016

CASS [Foucar et al. (2012). Comput. Phys. Commun.183, 2207-2213] is a well established software suite for experiments performed at any sort of light source. It is based on a modular design and can easily be adapted for use at free-electron laser (FEL) experiments that have a biological focus. This article will list all the additional functionality and enhancements of CASS for use with FEL experiments that have been introduced since the first publication. The article will also highlight some advanced experiments with biological aspects that have been performed.An overview of how the well established CFEL-ASG Software Suite (CASS) can be used for serial femtosecond crystallography data is given. © Lutz Foucar 2016.


Cryle M.J.,Max Planck Institute for Medical Research
Biochemical Society Transactions | Year: 2010

The cytochromes P450 (P450s) are a superfamily of oxidative haemoproteins that are capable of catalysing a vast range of oxidative transformations, including the oxidation of unactivated alkanes, often with high stereo- and regio-selectivity. Fatty acid hydroxylation by P450s is widespread across both bacteria and higher organisms, with the sites of oxidation and specificity of oxidation varying from system to system. Several key examples are discussed in the present article, with the focus on P450BioI (CYP107H1), a biosynthetic P450 found in the biotin operon of Bacillus subtilis. The biosynthetic function of P450BioI is the formation of pimelic acid, a biotin precursor, via a multiple-step oxidative cleavage of long-chain fatty acids. P450BioI is a member of an important subgroup of P450s that accept their substrates not free in solution, but rather presented by a separate carrier protein. Structural characterization of the P450BioI-ACP (acyl-carrier protein) complex has recently been performed, which has revealed the basis for the oxidation of the centre of the fatty acid chain. The P450 BioI-ACP structure is the first such P450-carrier protein complex to be characterized structurally, with important implications for other biosynthetically intriguing P450-carrier protein complexes. ©The Authors.


Haslinger K.,Max Planck Institute for Medical Research | Peschke M.,Max Planck Institute for Medical Research | Brieke C.,Max Planck Institute for Medical Research | Maximowitsch E.,Max Planck Institute for Medical Research | Cryle M.J.,Max Planck Institute for Medical Research
Nature | Year: 2015

Non-ribosomal peptide synthetase (NRPS) mega-enzyme complexes are modular assembly lines that are involved in the biosynthesis of numerous peptide metabolites independently of the ribosome. The multiple interactions between catalytic domains within the NRPS machinery are further complemented by additional interactions with external enzymes, particularly focused on the final peptide maturation process. An important class of NRPS metabolites that require extensive external modification of the NRPS-bound peptide are the glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin. These clinically relevant peptide antibiotics undergo cytochrome P450-catalysed oxidative crosslinking of aromatic side chains to achieve their final, active conformation. However, the mechanism underlying the recruitment of the cytochrome P450 oxygenases to the NRPS-bound peptide was previously unknown. Here we show, through in vitro studies, that the X-domain, a conserved domain of unknown function present in the final module of all GPA NRPS machineries, is responsible for the recruitment of oxygenases to the NRPS-bound peptide to perform the essential side-chain crosslinking. X-ray crystallography shows that the X-domain is structurally related to condensation domains, but that its amino acid substitutions render it catalytically inactive. We found that the X-domain recruits cytochrome P450 oxygenases to the NRPS and determined the interface by solving the structure of a P450-X-domain complex. Additionally, we demonstrated that the modification of peptide precursors by oxygenases in vitro - in particular the installation of the second crosslink in GPA biosynthesis - occurs only in the presence of the X-domain. Our results indicate that the presentation of peptidyl carrier protein (PCP)-bound substrates for oxidation in GPA biosynthesis requires the presence of the NRPS X-domain to ensure conversion of the precursor peptide into a mature aglycone, and that the carrier protein domain alone is not always sufficient to generate a competent substrate for external cytochrome P450 oxygenases. © 2015 Macmillan Publishers Limited. All rights reserved.


Domratcheva T.,Max Planck Institute for Medical Research
Journal of the American Chemical Society | Year: 2011

The two major UV-induced DNA lesions, the cyclobutane pyrimidine dimers (CPD) and (6-4) pyrimidine-pyrimidone photoproducts, can be repaired by the light-activated enzymes CPD and (6-4) photolyases, respectively. It is a long-standing question how the two classes of photolyases with alike molecular structure are capable of reversing the two chemically different DNA photoproducts. In both photolyases the repair reaction is initiated by photoinduced electron transfer from the hydroquinone-anion part of the flavin adenine dinucleotide (FADH -) cofactor to the photoproduct. Here, the state-of-the-art XMCQDPT2-CASSCF approach was employed to compute the excitation spectra of the respective active site models. It is found that protonation of His365 in the presence of the hydroquinone-anion electron donor causes spontaneous, as opposed to photoinduced, coupled proton and electron transfer to the (6-4) photoproduct. The resulting neutralized biradical, containing the neutral semiquinone and the N3′-protonated (6-4) photoproduct neutral radical, corresponds to the lowest energy electronic ground-state minimum. The high electron affinity of the N3′-protonated (6-4) photoproduct underlines this finding. Thus, it is anticipated that the (6-4) photoproduct repair is assisted by His365 in its neutral form, which is in contrast to the repair mechanisms proposed in the literature. The repair via hydroxyl group transfer assisted by neutral His365 is considered. The repair involves the 5′base radical anion of the (6-4) photoproduct which in terms of electronic structure is similar to the CPD radical anion. A unified model of the CPD and (6-4) photoproduct repair is proposed. © 2011 American Chemical Society.


Mikula S.,Max Planck Institute for Medical Research | Binding J.,Max Planck Institute for Medical Research | Denk W.,Max Planck Institute for Medical Research
Nature Methods | Year: 2012

The development of methods for imaging large contiguous volumes with the electron microscope could allow the complete mapping of a whole mouse brain at the single-axon level. We developed a method based on prolonged immersion that enables staining and embedding of the entire mouse brain with uniform myelin staining and a moderate preservation of the tissue's ultrastructure. We tested the ability to follow myelinated axons using serial block-face electron microscopy. © 2012 Nature America, Inc. All rights reserved.

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