FMP Publications

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

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References

2017

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
Rathjen(*), T., Yan(*), X., Kononenko, N. L., Ku(*), M. C., Song(*), K., Ferrarese(*), L., Tarallo(*), V., Puchkov, D., Kochlamazashvili, G., Brachs(*), S., Varela(*), L., Szigeti-Buck(*), K., Yi(*), C. X., Schriever(*), S. C., Tattikota(*), S. G., Carlo(*), A. S., Moroni(*), M., Siemens(*), J., Heuser(*), A., van der Weyden(*), L., Birkenfeld(*), A. L., Niendorf(*), T., Poulet(*), J. F. A., Horvath(*), T. L., Tschop(*), M. H., Heinig(*), M., Trajkovski(*), M., Haucke, V.; Poy(*), M. N.
Nat Neurosci,
(2017)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Cellular Imaging (Wiesner, Puchkov)

Abstract: Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.

Unambiguous Identification of Serine and Threonine Pyrophosphorylation Using Neutral-Loss-Triggered Electron-Transfer/Higher-Energy Collision Dissociation
Penkert, M., Yates(*), L. M., Schümann, M., Perlman(*), D., Fiedler, D.; Krause, E.
Anal Chem, 89:3672-3680
(2017)

Tags: Mass Spectrometry (Krause, E.), Chemical Biology I (Fiedler)

Abstract: Tandem mass spectrometry (MS/MS) has emerged as the core technology for identification of post-translational modifications (PTMs). Here, we report the mass spectrometry analysis of serine and threonine pyrophosphorylation, a protein modification that has eluded detection by conventional MS/MS methods. Analysis of a set of synthesized, site-specifically modified peptides by different fragmentation techniques shows that pyrophosphorylated peptides exhibit a characteristic neutral loss pattern of 98, 178, and 196 Da, which enables the distinction between isobaric pyro- and diphosphorylated peptides. In addition, electron-transfer dissociation combined with higher energy collision dissociation (EThcD) provides exceptional data-rich MS/MS spectra for direct and unambiguous pyrophosphosite assignment. Remarkably, sufficient fragmentation of doubly charged precursors could be achieved by electron-transfer dissociation (ETD) with increased supplemental activation, without losing the labile modification. By exploiting the specific fragmentation behavior of pyrophosphorylated peptides during collision-induced dissociation (CID), a data dependent neutral-loss-triggered EThcD acquisition method was developed. This strategy enables reliable pyrophosphopeptide identification in complex samples, without compromising speed and sensitivity.

Gamma oscillations organize top-down signalling to hypothalamus and enable food seeking
Carus-Cadavieco, M., Gorbati, M., Ye(*), L., Bender, F., van der Veldt, S., Kosse(*), C., Borgers(*), C., Lee(*), S. Y., Ramakrishnan(*), C., Hu, Y., Denisova, N., Ramm, F., Volitaki, E., Burdakov(*), D., Deisseroth(*), K., Ponomarenko, A.; Korotkova, T.
Nature, 542:232-236
(2017)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Both humans and animals seek primary rewards in the environment, even when such rewards do not correspond to current physiological needs. An example of this is a dissociation between food-seeking behaviour and metabolic needs, a notoriously difficult-to-treat symptom of eating disorders. Feeding relies on distinct cell groups in the hypothalamus, the activity of which also changes in anticipation of feeding onset. The hypothalamus receives strong descending inputs from the lateral septum, which is connected, in turn, with cortical networks, but cognitive regulation of feeding-related behaviours is not yet understood. Cortical cognitive processing involves gamma oscillations, which support memory, attention, cognitive flexibility and sensory responses. These functions contribute crucially to feeding behaviour by unknown neural mechanisms. Here we show that coordinated gamma (30-90 Hz) oscillations in the lateral hypothalamus and upstream brain regions organize food-seeking behaviour in mice. Gamma-rhythmic input to the lateral hypothalamus from somatostatin-positive lateral septum cells evokes food approach without affecting food intake. Inhibitory inputs from the lateral septum enable separate signalling by lateral hypothalamus neurons according to their feeding-related activity, making them fire at distinct phases of the gamma oscillation. Upstream, medial prefrontal cortical projections provide gamma-rhythmic inputs to the lateral septum; these inputs are causally associated with improved performance in a food-rewarded learning task. Overall, our work identifies a top-down pathway that uses gamma synchronization to guide the activity of subcortical networks and to regulate feeding behaviour by dynamic reorganization of functional cell groups in the hypothalamus.

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma
Du(*), J., Neuenschwander, M., Yu(*), Y., Dabritz(*), J. H., Neuendorff(*), N. R., Schleich(*), K., Bittner(*), A., Milanovic(*), M., Beuster(*), G., Radetzki, S., Specker, E., Reimann(*), M., Rosenbauer(*), F., Mathas(*), S., Lohneis(*), P., Hummel(*), M., Dörken(*), B., von Kries, J. P., Lee(*), S.; Schmitt(*), C. A.
Blood, 129:71-81
(2017)

Tags: Screening Unit (von Kries)

Abstract: Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL.

Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI
Lakshmanan(*), A., Lu(*), G. J., Farhadi(*), A., Nety(*), S. P., Kunth, M., Lee-Gosselin(*), A., Maresca(*), D., Bourdeau(*), R. W., Yin(*), M., Yan(*), J., Witte, C., Malounda(*), D., Foster(*), F. S., Schröder, L.; Shapiro(*), M. G.
Nat Protoc, 12:2050-2080
(2017)

Tags: Molecular Imaging (Schröder)

Abstract: Gas vesicles (GVs) are a unique class of gas-filled protein nanostructures that are detectable at subnanomolar concentrations and whose physical properties allow them to serve as highly sensitive imaging agents for ultrasound and MRI. Here we provide a protocol for isolating GVs from native and heterologous host organisms, functionalizing these nanostructures with moieties for targeting and fluorescence, characterizing their biophysical properties and imaging them using ultrasound and MRI. GVs can be isolated from natural cyanobacterial and haloarchaeal host organisms or from Escherichia coli expressing a heterologous GV gene cluster and purified using buoyancy-assisted techniques. They can then be modified by replacing surface-bound proteins with engineered, heterologously expressed variants or through chemical conjugation, resulting in altered mechanical, surface and targeting properties. Pressurized absorbance spectroscopy is used to characterize their mechanical properties, whereas dynamic light scattering (DLS)and transmission electron microscopy (TEM) are used to determine nanoparticle size and morphology, respectively. GVs can then be imaged with ultrasound in vitro and in vivo using pulse sequences optimized for their detection versus background. They can also be imaged with hyperpolarized xenon MRI using chemical exchange saturation transfer between GV-bound and dissolved xenon-a technique currently implemented in vitro. Taking 3-8 d to prepare, these genetically encodable nanostructures enable multimodal, noninvasive biological imaging with high sensitivity and potential for molecular targeting.

An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling
Mertins(*), P., Przybylski(*), D., Yosef(*), N., Qiao(*), J., Clauser(*), K., Raychowdhury(*), R., Eisenhaure(*), T. M., Maritzen, T., Haucke, V., Satoh(*), T., Akira(*), S., Carr(*), S. A., Regev(*), A., Hacohen(*), N.; Chevrier(*), N.
Cell Rep, 19:2853-2866
(2017)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Membrane Traffic and Cell Motility (Maritzen)

Abstract: Building an integrated view of cellular responses to environmental cues remains a fundamental challenge due to the complexity of intracellular networks in mammalian cells. Here, we introduce an integrative biochemical and genetic framework to dissect signal transduction events using multiple data types and, in particular, to unify signaling and transcriptional networks. Using the Toll-like receptor (TLR) system as a model cellular response, we generate multifaceted datasets on physical, enzymatic, and functional interactions and integrate these data to reveal biochemical paths that connect TLR4 signaling to transcription. We define the roles of proximal TLR4 kinases, identify and functionally test two dozen candidate regulators, and demonstrate a role for Ap1ar (encoding the Gadkin protein) and its binding partner, Picalm, potentially linking vesicle transport with pro-inflammatory responses. Our study thus demonstrates how deciphering dynamic cellular responses by integrating datasets on various regulatory layers defines key components and higher-order logic underlying signaling-to-transcription pathways.

2016

Specific binding of a mutated fragment of Clostridium perfringens enterotoxin to endothelial claudin-5 and its modulation of cerebral vascular permeability
Liao(*), Z., Yang(*), Z., Piontek, A., Eichner(*), M., Krause, G., Li(*), L., Piontek(*), J.; Zhang(*), J.
Neuroscience, 327:53-63
(2016)

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

Abstract: The vertebrate blood-brain barrier (BBB) creates an obstacle for central nervous system-related drug delivery. Claudin-5 (Cldn5), expressed in large quantities in BBB, plays a vital role in restricting BBB permeability. The C-terminal domain of Clostridium perfringens enterotoxin (cCPE) has been verified as binding to a subset of claudins (Cldns). The Cldn5-binding cCPE194-319 variant cCPEY306W/S313H was applied in this study to investigate its ability to modulate the permeability of zebrafish larval BBB. In vitro results showed that cCPEY306W/S313H is able to bind specifically to Cldn5 in murine brain vascular endothelial (bEnd.3) cells, and is transported along with Cldn5 from the cell membrane to the cytoplasm, which in turn results in a reduction in transendothelial electrical resistance (TEER). Conversely, this effect can be reversed by removal of cCPEY306W/S313H. In an in vivo experiment, this study estimates the capability of cCPEY306W/S313H to modulate Cldn5 using a rhodamine B-Dextran dye diffusion assay in zebrafish larval BBB. The results show that cCPEY306W/S313H co-localized with Cldn5 in zebrafish cerebral vascular cells and modulated BBB permeability, resulting in dye leakage. Taken together, this study suggests that cCPEY306W/S313H has the capability - both in vitro and in vivo - to modulate BBB permeability temporarily by specific binding to Cldn5.

A Stable Pyrophosphoserine Analog for Incorporation into Peptides and Proteins
Yates(*), L. M.; Fiedler, D.
ACS Chem Biol, 11:1066-1073
(2016)

Tags: Chemical Biology I (Fiedler)

Abstract: Protein pyrophosphorylation is a covalent modification of proteins, mediated by the inositol pyrophosphate messengers. Although the inositol pyrophosphates have been linked to a range of cellular processes, the role of protein pyrophosphorylation remains minimally characterized in vivo. The inherent instability of the phosphoanhydride bond has hampered the development of useful bioanalytical techniques to interrogate this novel signaling mechanism. Here, we describe the preparation of a pyrophosphoserine analog containing a stable methylene-bisphosphonate group that is compatible with solid-phase peptide synthesis. The resulting peptides demonstrate enhanced stability in Eukaryotic cell lysates and mammalian plasma and display resistance toward chemical degradation, when compared to the corresponding pyrophosphopeptides. In addition, the peptides containing the stable pyrophosphoserine analog are highly compatible with common ligation methods, such as native chemical ligation, maleimide conjugation, and glutaraldehyde ligation. The bisphosphonate-containing peptides will, therefore, be well-suited for future pyrophosphoserine antibody generation and affinity capture of pyrophosphoprotein binding partners and provide a key entry point to study the regulatory role of protein pyrophosphorylation.

2015

Simian hemorrhagic fever virus cell entry is dependent on CD163 and uses a clathrin-mediated endocytosis-like pathway
Cai(*), Y., Postnikova(*), E. N., Bernbaum(*), J. G., Yu(*), S. Q., Mazur(*), S., Deiuliis(*), N. M., Radoshitzky(*), S. R., Lackemeyer(*), M. G., McCluskey(*), A., Robinson(*), P. J., Haucke, V., Wahl-Jensen(*), V., Bailey(*), A. L., Lauck(*), M., Friedrich(*), T. C., O'Connor(*), D. H., Goldberg(*), T. L., Jahrling(*), P. B.; Kuhn(*), J. H.
J Virol, 89:844-856
(2015)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: UNLABELLED: Simian hemorrhagic fever virus (SHFV) causes a severe and almost uniformly fatal viral hemorrhagic fever in Asian macaques but is thought to be nonpathogenic for humans. To date, the SHFV life cycle is almost completely uncharacterized on the molecular level. Here, we describe the first steps of the SHFV life cycle. Our experiments indicate that SHFV enters target cells by low-pH-dependent endocytosis. Dynamin inhibitors, chlorpromazine, methyl-beta-cyclodextrin, chloroquine, and concanamycin A dramatically reduced SHFV entry efficiency, whereas the macropinocytosis inhibitors EIPA, blebbistatin, and wortmannin and the caveolin-mediated endocytosis inhibitors nystatin and filipin III had no effect. Furthermore, overexpression and knockout study and electron microscopy results indicate that SHFV entry occurs by a dynamin-dependent clathrin-mediated endocytosis-like pathway. Experiments utilizing latrunculin B, cytochalasin B, and cytochalasin D indicate that SHFV does not hijack the actin polymerization pathway. Treatment of target cells with proteases (proteinase K, papain, alpha-chymotrypsin, and trypsin) abrogated entry, indicating that the SHFV cell surface receptor is a protein. Phospholipases A2 and D had no effect on SHFV entry. Finally, treatment of cells with antibodies targeting CD163, a cell surface molecule identified as an entry factor for the SHFV-related porcine reproductive and respiratory syndrome virus, diminished SHFV replication, identifying CD163 as an important SHFV entry component. IMPORTANCE: Simian hemorrhagic fever virus (SHFV) causes highly lethal disease in Asian macaques resembling human illness caused by Ebola or Lassa virus. However, little is known about SHFV's ecology and molecular biology and the mechanism by which it causes disease. The results of this study shed light on how SHFV enters its target cells. Using electron microscopy and inhibitors for various cellular pathways, we demonstrate that SHFV invades cells by low-pH-dependent, actin-independent endocytosis, likely with the help of a cellular surface protein.

Untangling a Repetitive Amyloid Sequence: Correlating Biofilm-Derived and Segmentally Labeled Curli Fimbriae by Solid-State NMR Spectroscopy
Schubeis(*), T., Yuan(*), P., Ahmed(*), M., Nagaraj, M., van Rossum, B. J.; Ritter(*), C.
Angew Chem Int Ed Engl, 54:14669-14672
(2015)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Curli are functional bacterial amyloids produced by an intricate biogenesis machinery. Insights into their folding and regulation can advance our understanding of amyloidogenesis. However, gaining detailed structural information of amyloids, and their tendency for structural polymorphisms, remains challenging. Herein we compare high-quality solid-state NMR spectra from biofilm-derived and recombinantly produced curli and provide evidence that they adopt a similar, well-defined beta-solenoid arrangement. Curli subunits consist of five sequence repeats, resulting in severe spectral overlap. Using segmental isotope labeling, we obtained the unambiguous sequence-specific resonance assignments and secondary structure of one repeat, and demonstrate that all repeats are most likely structurally equivalent.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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info(at)fmp-berlin.de

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