FMP Publications

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

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Temperature dependence of cross-effect dynamic nuclear polarization in rotating solids: advantages of elevated temperatures
Geiger, M. A., Orwick-Rydmark, M., Marker, K., Franks, W. T., Akhmetzyanov(*), D., Stöppler, D., Zinke, M., Specker, E., Nazare, M., Diehl, A., van Rossum, B. J., Aussenac(*), F., Prisner(*), T., Akbey, Ü.; Oschkinat, H.
Phys Chem Chem Phys, 18:30696-30704

Tags: NMR-Supported Structural Biology (Oschkinat), Medicinal Chemistry (Nazare), Molecular Biophysics (Lange, A.)

Abstract: Dynamic nuclear polarization exploits electron spin polarization to boost signal-to-noise in magic-angle-spinning (MAS) NMR, creating new opportunities in materials science, structural biology, and metabolomics studies. Since protein NMR spectra recorded under DNP conditions can show improved spectral resolution at 180-200 K compared to 110 K, we investigate the effects of AMUPol and various deuterated TOTAPOL isotopologues on sensitivity and spectral resolution at these temperatures, using proline and reproducibly prepared SH3 domain samples. The TOTAPOL deuteration pattern is optimized for protein DNP MAS NMR, and signal-to-noise per unit time measurements demonstrate the high value of TOTAPOL isotopologues for Protein DNP MAS NMR at 180-200 K. The combined effects of enhancement, depolarization, and proton longitudinal relaxation are surprisingly sample-specific. At 200 K, DNP on SH3 domain standard samples yields a 15-fold increase in signal-to-noise over a sample without radicals. 2D and 3D NCACX/NCOCX spectra were recorded at 200 K within 1 and 13 hours, respectively. Decreasing enhancements with increasing 2H-content at the CH2 sites of the TEMPO rings in CD3-TOTAPOL highlight the importance of protons in a sphere of 4-6 A around the nitroxyl group, presumably for polarization pickup from electron spins.

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.

Tubular Epithelial NF-kappaB Activity Regulates Ischemic AKI
Marko(*), L., Vigolo(*), E., Hinze(*), C., Park(*), J. K., Roel(*), G., Balogh(*), A., Choi(*), M., Wübken(*), A., Cording, J., Blasig, I. E., Luft(*), F. C., Scheidereit(*), C., Schmidt-Ott(*), K. M., Schmidt-Ullrich(*), R.; Müller(*), D. N.
Journal of the American Society of Nephrology : JASN, 27:2658-2669

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

Abstract: NF-kappaB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type-specific functions of NF-kappaB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-kappaB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-kappaB reporter activity and nuclear localization of phosphorylated NF-kappaB subunit p65 analyses in mice revealed that IRI induced widespread NF-kappaB activation in renal tubular epithelia and in interstitial cells that peaked 2-3 days after injury. To genetically antagonize tubular epithelial NF-kappaB activity, we generated mice expressing the human NF-kappaB super-repressor IkappaBalphaDeltaN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-kappaB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IkappaBalphaDeltaN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-kappaB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females
Palmer(*), E. E., Stuhlmann, T., Weinert, S., Haan(*), E., Van Esch(*), H., Holvoet(*), M., Boyle(*), J., Leffler(*), M., Raynaud(*), M., Moraine(*), C., van Bokhoven(*), H., Kleefstra(*), T., Kahrizi(*), K., Najmabadi(*), H., Ropers(*), H. H., Delgado(*), M. R., Sirsi(*), D., Golla(*), S., Sommer(*), A., Pietryga(*), M. P., Chung(*), W. K., Wynn(*), J., Rohena(*), L., Bernardo(*), E., Hamlin(*), D., Faux(*), B. M., Grange(*), D. K., Manwaring(*), L., Tolmie(*), J., Joss(*), S., Cobben(*), J. M., Duijkers(*), F. A., Goehringer(*), J. M., Challman(*), T. D., Hennig(*), F., Fischer(*), U., Grimme(*), A., Suckow(*), V., Musante(*), L., Nicholl(*), J., Shaw(*), M., Lodh(*), S. P., Niu(*), Z., Rosenfeld(*), J. A., Stankiewicz(*), P., Jentsch, T. J., Gecz(*), J., Field(*), M.; Kalscheuer(*), V. M.
Molecular psychiatry,

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.Molecular Psychiatry advance online publication, 23 August 2016; doi:10.1038/mp.2016.135.

A Complex of Htm1 and the Oxidoreductase Pdi1 Accelerates Degradation of Misfolded Glycoproteins
Pfeiffer(*), A., Stephanowitz, H., Krause, E., Volkwein(*), C., Hirsch(*), C., Jarosch(*), E.; Sommer(*), T.
J Biol Chem, 291:12195-12207

Tags: Mass Spectrometry (Krause, E.)

Abstract: A quality control system in the endoplasmic reticulum (ER) efficiently discriminates polypeptides that are in the process of productive folding from conformers that are trapped in an aberrant state. Only the latter are transported into the cytoplasm and degraded in a process termed ER-associated protein degradation (ERAD). In the ER, an enzymatic cascade generates a specific N-glycan structure of seven mannosyl and two N-acetylglucosamine residues (Man7GlcNAc2) on misfolded glycoproteins to facilitate their disposal. We show that a complex encompassing the yeast lectin-like protein Htm1 and the oxidoreductase Pdi1 converts Man8GlcNAc2 on glycoproteins into the Man7GlcNAc2 signal. In vitro the Htm1-Pdi1 complex processes both unfolded and native proteins albeit with a preference for the former. In vivo, elevated expression of HTM1 causes glycan trimming on misfolded and folded proteins, but only degradation of the non-native species is accelerated. Thus, modification with a Man7GlcNAc2 structure does not inevitably commit a protein for ER-associated protein degradation. The function of Htm1 in ERAD relies on its association with Pdi1, which appears to regulate the access to substrates. Our data support a model in which the balanced activities of Pdi1 and Htm1 are crucial determinants for the efficient removal of misfolded secretory glycoproteins.

Ultrafast Magic-Angle Spinning: Benefits for the Acquisition of Ultrawide-Line NMR Spectra of Heavy Spin-1/2 Nuclei
Pöppler, A. C., Demers, J. P., Malon(*), M., Singh(*), A. P., Roesky(*), H. W., Nishiyama(*), Y.; Lange, A.
Chemphyschem, 17:812-816

Tags: Molecular Biophysics (Lange, A.)

Abstract: The benefits of the ultrafast magic-angle spinning (MAS) approach for the acquisition of ultrawide-line NMR spectra-spectral simplification, increased mass sensitivity allowing the fast study of small amounts of material, efficient excitation, and application to multiple heavy nuclei-are demonstrated for tin(II) oxide (SnO) and the tin complex [(LB)Sn(II) Cl](+) [Sn(II) Cl3 ](-) [LB=2,6-diacetylpyridinebis(2,6-diisopropylanil)] containing two distinct tin environments. The ultrafast MAS experiments provide optimal conditions for the extraction of the chemical-shift anisotropy tensor parameters, anisotropy, and asymmetry for heavy spin-1/2 nuclei.

Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-beta Peptide Which Exhibit Reduced Neurotoxicity
Prade(*), E., Barucker(*), C., Sarkar(*), R., Althoff-Ospelt(*), G., Lopez del Amo, J. M., Hossain(*), S., Zhong(*), Y., Multhaup(*), G.; Reif(*), B.
Biochemistry, 55:1839-1849

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Alzheimer's disease is characterized by deposition of the amyloid beta-peptide (Abeta) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Abeta peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Abeta solution. We find that sulindac sulfide induced Abeta aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a beta-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Abeta peptide in the aggregate.

Effects of Halide Ions on the Carbamidocyclophane Biosynthesis in Nostoc sp. CAVN2
Preisitsch(*), M., Heiden(*), S. E., Beerbaum, M., Niedermeyer(*), T. H., Schneefeld(*), M., Herrmann(*), J., Kumpfmüller(*), J., Thürmer(*), A., Neidhardt(*), I., Wiesner(*), C., Daniel(*), R., Müller(*), R., Bange(*), F. C., Schmieder, P., Schweder(*), T.; Mundt(*), S.
Mar Drugs, 14:21

Tags: Solution NMR (Schmieder)

Abstract: In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M-U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.

Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms
Wu(*), M., Chong, L. S., Perlman(*), D. H., Resnick(*), A. C.; Fiedler, D.
Proc Natl Acad Sci U S A, 113:E6757-E6765

Tags: Chemical Biology I (Fiedler)

Abstract: Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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