FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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Organophosphorus-mediated N-N bond formation: facile access to 3-amino-2H-indazoles
Bel Abed, H., Schöne, J., Christmann(*), M.; Nazare, M.
Org Biomol Chem, 14:8520-8528

Tags: Medicinal Chemistry (Nazare)

Abstract: A convenient and efficient strategy has been devised to access 3-amino-2H-indazole derivatives in two steps from readily available starting materials. The conversion of 2-nitrobenzonitriles to substituted benzamidines followed by an organophosphorus-mediated reductive cyclization and a subsequent N-N bond formation afforded 3-amino-2H-indazoles in good to excellent yields.

Reversible Opening of Intercellular Junctions of Intestinal Epithelial and Brain Endothelial Cells With Tight Junction Modulator Peptides
Bocsik(*), A., Walter(*), F. R., Gyebrovszki(*), A., Fulop(*), L., Blasig, I., Dabrowski, S., Otvos(*), F., Toth(*), A., Rakhely(*), G., Veszelka(*), S., Vastag(*), M., Szabo-Revesz(*), P.; Deli(*), M. A.
Journal of pharmaceutical sciences, 105:754-765

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: The intercellular junctions restrict the free passage of hydrophilic compounds through the paracellular clefts. Reversible opening of the tight junctions of biological barriers is investigated as one of the ways to increase drug delivery to the systemic circulation or the central nervous system. Six peptides, ADT-6, HAV-6, C-CPE, 7-mer (FDFWITP, PN-78), AT-1002, and PN-159, acting on different integral membrane and linker junctional proteins were tested on Caco-2 intestinal epithelial cell line and a coculture model of the blood-brain barrier. All peptides tested in nontoxic concentrations showed a reversible tight junctions modulating effect and were effective to open the paracellular pathway for the marker molecules fluorescein and albumin. The change in the structure of cell-cell junctions was verified by immunostaining for occludin, claudin-4,-5, ZO-1, beta-catenin, and E-cadherin. Expression levels of occludin and claudins were measured in both models. We could demonstrate a selectivity of C-CPE, ADT-6, and HAV-6 peptides for epithelial cells and 7-mer and AT-1002 peptides for brain endothelial cells. PN-159 was the most effective modulator of junctional permeability in both models possibly acting via claudin-1 and -5. Our results indicate that these peptides can be effectively and selectively used as potential pharmaceutical excipients to improve drug delivery across biological barriers.

Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling
Böhme(*), M. A., Beis(*), C., Reddy-Alla(*), S., Reynolds(*), E., Mampell(*), M. M., Grasskamp, A. T., Lutzkendorf(*), J., Bergeron(*), D. D., Driller(*), J. H., Babikir(*), H., Göttfert(*), F., Robinson(*), I. M., O'Kane(*), C. J., Hell(*), S. W., Wahl(*), M. C., Stelzl(*), U., Loll(*), B., Walter, A. M.; Sigrist(*), S. J.
Nat Neurosci, 19:1311-1320

Tags: Molecular and Theoretical Neuroscience (Walter)

Abstract: Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca(2+) channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-alpha, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.

On The Potential of Dynamic Nuclear Polarization Enhanced Diamonds in Solid-State and Dissolution (13) C NMR Spectroscopy
Bretschneider(*), C. O., Akbey, Ü., Aussenac(*), F., Olsen(*), G. L., Feintuch(*), A., Oschkinat, H.; Frydman(*), L.
Chemphyschem, 17:2691-2701

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Dynamic nuclear polarization (DNP) is a versatile option to improve the sensitivity of NMR and MRI. This versatility has elicited interest for overcoming potential limitations of these techniques, including the achievement of solid-state polarization enhancement at ambient conditions, and the maximization of (13) C signal lifetimes for performing in vivo MRI scans. This study explores whether diamond's (13) C behavior in nano- and micro-particles could be used to achieve these ends. The characteristics of diamond's DNP enhancement were analyzed for different magnetic fields, grain sizes, and sample environments ranging from cryogenic to ambient temperatures, in both solution and solid-state experiments. It was found that (13) C NMR signals could be boosted by orders of magnitude in either low- or room-temperature solid-state DNP experiments by utilizing naturally occurring paramagnetic P1 substitutional nitrogen defects. We attribute this behavior to the unusually long electronic/nuclear spin-lattice relaxation times characteristic of diamond, coupled with a time-independent cross-effect-like polarization transfer mechanism facilitated by a matching of the nitrogen-related hyperfine coupling and the (13) C Zeeman splitting. The efficiency of this solid-state polarization process, however, is harder to exploit in dissolution DNP-enhanced MRI contexts. The prospects for utilizing polarized diamond approaching nanoscale dimensions for both solid and solution applications are briefly discussed.

Chemical tools for interrogating inositol pyrophosphate structure and function
Brown, N. W., Marmelstein, A. M.; Fiedler, D.
Chem Soc Rev, 45:6311-6326

Tags: Chemical Biology I (Fiedler)

Abstract: The inositol pyrophosphates (PP-InsPs) are a unique group of intracellular messengers that represent some of the most highly phosphorylated molecules in nature. Genetic perturbation of the PP-InsP biosynthetic network indicates a central role for these metabolites in maintaining cellular energy homeostasis and in controlling signal transduction networks. However, despite their discovery over two decades ago, elucidating their physiologically relevant isomers, the biochemical pathways connecting these molecules to their associated phenotypes, and their modes of signal transduction has often been stymied by technical challenges. Many of the advances in understanding these molecules to date have been facilitated by the total synthesis of the various PP-InsP isomers and by the development of new methods that are capable of identifying their downstream signalling partners. Chemical tools have also been developed to distinguish between the proposed PP-InsP signal transduction mechanisms: protein binding, and a covalent modification of proteins termed protein pyrophosphorylation. In this article, we review these recent developments, discuss how they have helped to illuminate PP-InsP structure and function, and highlight opportunities for future discovery.

Elm defence against herbivores and pathogens: morphological, chemical and molecular regulation aspects
Buchel(*), K., Fenning(*), T., Gershenzon(*), J., Hilker(*), M.; Meiners, T.
Phytochem Rev, 15:961-983

Tags: Department Chemical Biology/ EU-OPENSCREEN

Abstract: Elms (Ulmus spp.) have long been appreciated for their environmental tolerance, landscape and ornamental value, and the quality of their wood. Although elm trees are extremely hardy against abiotic stresses such as wind and pollution, they are susceptible to attacks of biotic stressors. Over 100 phytopathogens and invertebrate pests are associated with elms: fungi, bacteria and insects like beetles and moths, and to a lesser extent aphids, mites, viruses and nematodes. While the biology of the pathogen and insect vector of the Dutch elm disease has been intensively studied, less attention has been paid so far to the defence mechanisms of elms to other biotic stressors. This review highlights knowledge of direct and indirect elm defences against biotic stressors focusing on morphological, chemical and gene regulation aspects. First, we report how morphological defence mechanisms via barrier formation and vessel occlusion prevent colonisation and spread of wood- and bark-inhabiting fungi and bacteria. Second, we outline how secondary metabolites such as terpenoids (volatile terpenoids, mansonones and triterpenoids) and phenolics (lignans, coumarins, flavonoids) in leaves and bark are involved in constitutive and induced chemical defence mechanisms of elms. Third, we address knowledge on how the molecular regulation of elm defence is orchestrated through the interaction of a huge variety of stress- and defence-related genes. We conclude by pointing to the gaps of knowledge on the chemical and molecular mechanisms of elm defence against pest insects and diseases. An in-depth understanding of defence mechanisms of elms will support the development of sustainable integrated management of pests and diseases attacking elms.

Bimodal antagonism of PKA signalling by ARHGAP36
Eccles(*), R. L., Czajkowski(*), M. T., Barth(*), C., Müller(*), P. M., McShane(*), E., Grunwald(*), S., Beaudette(*), P., Mecklenburg(*), N., Volkmer, R., Zühlke(*), K., Dittmar(*), G., Selbach(*), M., Hammes(*), A., Daumke(*), O., Klussmann(*), E., Urbe(*), S.; Rocks(*), O.
Nat Commun, 7:12963

Tags: Peptide Synthesis (Hackenberger/Volkmer)

Abstract: Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors. ARHGAP36 thus dampens the sensitivity of cells to cAMP. We show that PKA inhibition by ARHGAP36 promotes derepression of the Hedgehog signalling pathway, thereby providing a simple rationale for the upregulation of ARHGAP36 in medulloblastoma. Our work reveals a new layer of PKA regulation that may play an important role in development and disease.

Identification of Novel Nuclear Factor of Activated T Cell (NFAT)-associated Proteins in T Cells
Gabriel(*), C. H., Gross(*), F., Karl(*), M., Stephanowitz, H., Hennig(*), A. F., Weber(*), M., Gryzik(*), S., Bachmann(*), I., Hecklau(*), K., Wienands(*), J., Schuchhardt(*), J., Herzel(*), H., Radbruch(*), A., Krause, E.; Baumgrass(*), R.
J Biol Chem, 291:24172-24187

Tags: Mass Spectrometry (Krause, E.)

Abstract: Transcription factors of the nuclear factor of activated T cell (NFAT) family are essential for antigen-specific T cell activation and differentiation. Their cooperative DNA binding with other transcription factors, such as AP1 proteins (FOS, JUN, and JUNB), FOXP3, IRFs, and EGR1, dictates the gene regulatory action of NFATs. To identify as yet unknown interaction partners of NFAT, we purified biotin-tagged NFATc1/alphaA, NFATc1/betaC, and NFATc2/C protein complexes and analyzed their components by stable isotope labeling by amino acids in cell culture-based mass spectrometry. We revealed more than 170 NFAT-associated proteins, half of which are involved in transcriptional regulation. Among them are many hitherto unknown interaction partners of NFATc1 and NFATc2 in T cells, such as Raptor, CHEK1, CREB1, RUNX1, SATB1, Ikaros, and Helios. The association of NFATc2 with several other transcription factors is DNA-dependent, indicating cooperative DNA binding. Moreover, our computational analysis discovered that binding motifs for RUNX and CREB1 are found preferentially in the direct vicinity of NFAT-binding motifs and in a distinct orientation to them. Furthermore, we provide evidence that mTOR and CHEK1 kinase activity influence NFAT's transcriptional potency. Finally, our dataset of NFAT-associated proteins provides a good basis to further study NFAT's diverse functions and how these are modulated due to the interplay of multiple interaction partners.

AKAP18:PKA-RIIalpha structure reveals crucial anchor points for recognition of regulatory subunits of PKA
Götz, F., Roske(*), Y., Schulz(*), M. S., Autenrieth(*), K., Bertinetti(*), D., Faelber(*), K., Zühlke(*), K., Kreuchwig, A., Kennedy(*), E. J., Krause, G., Daumke(*), O., Herberg(*), F. W., Heinemann(*), U.; Klussmann(*), E.
Biochem J, 473:1881-1894

Tags: Structural Bioinformatics and Protein Design (Krause, G.), Anchored Signaling (Klussmann)

Abstract: A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18beta bound to the D/D domain of the regulatory RIIalpha subunits of PKA. We identified three hydrophilic anchor points in AKAP18beta outside the core PKA-binding domain, which mediate contacts with the D/D domain. Such anchor points are conserved within AKAPs that bind regulatory RII subunits of PKA. We derived a different set of anchor points in AKAPs binding regulatory RI subunits of PKA. In vitro and cell-based experiments confirm the relevance of these sites for the interaction of RII subunits with AKAP18 and of RI subunits with the RI-specific smAKAP. Thus we report a novel mechanism governing interactions of AKAPs with PKA. The sequence specificity of each AKAP around the anchor points and the requirement of these points for the tight binding of PKA allow the development of selective inhibitors to unequivocally ascribe cellular functions to the AKAP18-PKA and other AKAP-PKA interactions.

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses
Grauel(*), M. K., Maglione, M., Reddy-Alla(*), S., Willmes(*), C. G., Brockmann(*), M. M., Trimbuch(*), T., Rosenmund(*), T., Pangalos(*), M., Vardar(*), G., Stumpf(*), A., Walter, A. M., Rost(*), B. R., Eickholt(*), B. J., Haucke, V., Schmitz(*), D., Sigrist(*), S. J.; Rosenmund(*), C.
Proc Natl Acad Sci U S A, 113:11615-11620

Tags: Molecular Pharmacology and Cell Biology (Haucke), Molecular and Theoretical Neuroscience (Walter)

Abstract: The tight spatial coupling of synaptic vesicles and voltage-gated Ca2+ channels (CaVs) ensures efficient action potential-triggered neurotransmitter release from presynaptic active zones (AZs). Rab-interacting molecule-binding proteins (RIM-BPs) interact with Ca2+ channels and via RIM with other components of the release machinery. Although human RIM-BPs have been implicated in autism spectrum disorders, little is known about the role of mammalian RIM-BPs in synaptic transmission. We investigated RIM-BP2-deficient murine hippocampal neurons in cultures and slices. Short-term facilitation is significantly enhanced in both model systems. Detailed analysis in culture revealed a reduction in initial release probability, which presumably underlies the increased short-term facilitation. Superresolution microscopy revealed an impairment in CaV2.1 clustering at AZs, which likely alters Ca2+ nanodomains at release sites and thereby affects release probability. Additional deletion of RIM-BP1 does not exacerbate the phenotype, indicating that RIM-BP2 is the dominating RIM-BP isoform at these synapses.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
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