FMP Publications

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

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References
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
(2016)

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.

Green tea reduces body fat via upregulation of neprilysin
Muenzner, M., Tappenbeck(*), N., Gembardt(*), F., Rülke, R., Furkert, J., Melzig(*), M. F., Siems, W. E., Brockmann(*), G. A.; Walther(*), T.
Int J Obes (Lond), 40:1850-1855
(2016)

Tags: Biochemical Neurobiology (Siems)

Abstract: BACKGROUND/OBJECTIVE: Consumption of green tea has become increasingly popular, particularly because of claimed reduction in body weight. We recently reported that animals with pharmacological inhibition (by candoxatril) or genetic absence of the endopeptidase neprilysin (NEP) develop an obese phenotype. We now investigated the effect of green tea extract (in drinking water) on body weight and body composition and the mediating role of NEP. SUBJECTS/METHODS: To elucidate the role of NEP in mediating the beneficial effects of green tea extract, 'Berlin fat mice' or NEP-deficient mice and their age- and gender-matched wild-type controls received the extract in two different doses (300 or 600 mg kg-1 body weight per day) in the drinking water. RESULTS: In 'Berlin fat mice', 51 days of green tea treatment did not only prevent fat accumulation (control: day 0: 30.5% fat, day 51: 33.1%; NS) but also reduced significant body fat (green tea: day 0: 27.8%, day 51: 20.9%, P<0.01) and body weight below the initial levels. Green tea reduced food intake. This was paralleled by a selective increase in peripheral (in kidney 17%, in intestine 92%), but not central NEP expression and activity, leading to downregulation of orexigens (like galanin and neuropeptide Y (NPY)) known to be physiological substrates of NEP. Consequently, in NEP-knockout mice, green tea extract failed to reduce body fat/weight. CONCLUSIONS: Our data generate experimental proof for the assumed effects of green tea on body weight and the key role for NEP in such process, and thus open a new avenue for the treatment of obesity.

In-Cell Protein Structures from 2D NMR Experiments
Müntener(*), T., Haussinger(*), D., Selenko, P.; Theillet, F. X.
J Phys Chem Lett, 7:2821-2825
(2016)

Tags: In-Cell NMR (Selenko)

Abstract: In-cell NMR spectroscopy provides atomic resolution insights into the structural properties of proteins in cells, but it is rarely used to solve entire protein structures de novo. Here, we introduce a paramagnetic lanthanide-tag to simultaneously measure protein pseudocontact shifts (PCSs) and residual dipolar couplings (RDCs) to be used as input for structure calculation routines within the Rosetta program. We employ this approach to determine the structure of the protein G B1 domain (GB1) in intact Xenopus laevis oocytes from a single set of 2D in-cell NMR experiments. Specifically, we derive well-defined GB1 ensembles from low concentration in-cell NMR samples ( approximately 50 muM) measured at moderate magnetic field strengths (600 MHz), thus offering an easily accessible alternative for determining intracellular protein structures.

Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation
Mylona(*), A., Theillet, F. X., Foster(*), C., Cheng(*), T. M., Miralles(*), F., Bates(*), P. A., Selenko, P.; Treisman(*), R.
Science, 354:233-237
(2016)

Tags: In-Cell NMR (Selenko)

Abstract: Multisite phosphorylation regulates many transcription factors, including the serum response factor partner Elk-1. Phosphorylation of the transcriptional activation domain (TAD) of Elk-1 by the protein kinase ERK at multiple sites potentiates recruitment of the Mediator transcriptional coactivator complex and transcriptional activation, but the roles of individual phosphorylation events had remained unclear. Using time-resolved nuclear magnetic resonance spectroscopy, we found that ERK2 phosphorylation proceeds at markedly different rates at eight TAD sites in vitro, which we classified as fast, intermediate, and slow. Mutagenesis experiments showed that phosphorylation of fast and intermediate sites promoted Mediator interaction and transcriptional activation, whereas modification of slow sites counteracted both functions, thereby limiting Elk-1 output. Progressive Elk-1 phosphorylation thus ensures a self-limiting response to ERK activation, which occurs independently of antagonizing phosphatase activity.

Surface Binding of TOTAPOL Assists Structural Investigations of Amyloid Fibrils by Dynamic Nuclear Polarization NMR Spectroscopy
Nagaraj, M., Franks, T. W., Saeidpour(*), S., Schubeis(*), T., Oschkinat, H., Ritter(*), C.; van Rossum, B. J.
Chembiochem, 17:1308-1311
(2016)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Dynamic nuclear polarization (DNP) NMR can enhance sensitivity but often comes at the price of a substantial loss of resolution. Two major factors affect spectral quality: low-temperature heterogeneous line broadening and paramagnetic relaxation enhancement (PRE) effects. Investigations by NMR spectroscopy, isothermal titration calorimetry (ITC), and EPR revealed a new substantial affinity of TOTAPOL to amyloid surfaces, very similar to that shown by the fluorescent dye thioflavin-T (ThT). As a consequence, DNP spectra with remarkably good resolution and still reasonable enhancement could be obtained at very low TOTAPOL concentrations, typically 400 times lower than commonly employed. These spectra yielded several long-range constraints that were difficult to obtain without DNP. Our findings open up new strategies for structural studies with DNP NMR spectroscopy on amyloids that can bind the biradical with affinity similar to that shown towards ThT.

Inhibition of the key enzyme of sialic acid biosynthesis by C6-Se modified N-acetylmannosamine analogs
Nieto-Garcia, O., Wratil(*), P. R., Nguyen(*), L. D., Bohrsch(*), V., Hinderlich(*), S., Reutter(*), W.; Hackenberger, C. P. R.
Chem Sci, 7:3928-3933
(2016)

Tags: Chemical Biology II (Hackenberger)

Abstract: Synthetically accessible C6-analogs of N-acetylmannosamine (ManNAc) were tested as potential inhibitors of the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE/MNK), the key enzyme of sialic acid biosynthesis. Enzymatic experiments revealed that the modification introduced at the C6 saccharide position strongly influences the inhibitory potency. A C6-ManNAc diselenide dimer showed the strongest kinase inhibition in the low mu M range among all the substrates tested and successfully reduced cell surface sialylation in Jurkat cells.

Bis(arylmethyl)-substituted unsymmetrical phosphites for the synthesis of lipidated peptides via Staudinger-phosphite reactions
Nischan, N., Kasper, M. A., Mathew(*), T.; Hackenberger, C. P.
Org Biomol Chem, 14:7500-7508
(2016)

Tags: Chemical Biology II (Hackenberger)

Abstract: With this study we introduce new unsymmetrical phosphites to obtain lipidated peptide-conjugates starting from easily accessible azide-modified amino acid or peptide precursors. For this purpose, we investigated which substituents at alkyl phosphites lead to the highest formation of mono-alkylated phosphoramidate peptides. We found that phosphites containing one alkyl-chain and two picolyl or benzyl-substituents delivered alkyl phosphoramidate-conjugates in high yields, which also allowed a chemoselective lipidation of an unprotected azido polypeptide. Finally, monolipidated phosphoramidate peptides obtained by the unsymmetrical Staudinger phosphite reaction led to the formation of micelle-like structures and cellular uptake.

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,
(2016)

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
(2016)

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.

Single-Channel Recording of Ligand-Gated Ion Channels
Plested, A. J.
Cold Spring Harb Protoc, 2016:pdb top087239
(2016)

Tags: Molecular Neuroscience and Biophysics (Plested)

Abstract: Single-channel recordings reveal the microscopic properties of individual ligand-gated ion channels. Such recordings contain much more information than measurements of ensemble behavior and can yield structural and functional information about the receptors that participate in fast synaptic transmission in the brain. With a little care, a standard patch-clamp electrophysiology setup can be adapted for single-channel recording in a matter of hours. Thenceforth, it is a realistic aim to record single-molecule activity with microsecond resolution from arbitrary cell types, including cell lines and neurons.

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