FMP Publications

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

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References
Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission
Reddy-Alla(*), S., Böhme, M. A., Reynolds(*), E., Beis(*), C., Grasskamp, A. T., Mampell(*), M. M., Maglione, M., Jusyte, M., Rey(*), U., Babikir(*), H., McCarthy, A. W., Quentin(*), C., Matkovic(*), T., Bergeron(*), D. D., Mushtaq, Z., Goettfert(*), F., Owald(*), D., Mielke(*), T., Hell(*), S. W., Sigrist(*), S. J.; Walter, A. M.
Neuron,
(2017)

Tags: Molecular and Theoretical Neuroscience (Walter)

Abstract: Neural information processing depends on precisely timed, Ca2+-activated synaptic vesicle exocytosis from release sites within active zones (AZs), but molecular details are unknown. Here, we identify that the (M)Unc13-family member Unc13A generates release sites and show the physiological relevance of their restrictive AZ targeting. Super-resolution and intravital imaging of Drosophila neuromuscular junctions revealed that (unlike the other release factors Unc18 and Syntaxin-1A) Unc13A was stably and precisely positioned at AZs. Local Unc13A levels predicted single AZ activity. Different Unc13A portions selectively affected release site number, position, and functionality. An N-terminal fragment stably localized to AZs, displaced endogenous Unc13A, and reduced the number of release sites, while a C-terminal fragment generated excessive sites at atypical locations, resulting in reduced and delayed evoked transmission that displayed excessive facilitation. Thus, release site generation by the Unc13A C terminus and their specific AZ localization via the N terminus ensure efficient transmission and prevent ectopic, temporally imprecise release.

Targeting G-protein-coupled receptors by Capture Compound Mass Spectrometry (CCMS) - a case study with sertindole
Blex(*), C., Michaelis(*), S., Schrey(*), A. K., Furkert, J., Eichhorst, J., Bartho(*), K., Quast(*), F. G., Marais(*), A., Hakelberg(*), M., Gruber(*), U., Niquet(*), S., Popp(*), O., Kroll(*), F., Sefkow(*), M., Schülein, R., Mathias(*), D.; Koster(*), H.
Chembiochem, 18:1639-1649
(2017)

Tags: Protein Trafficking (Schülein), Cellular Imaging (Wiesner/Puchkov)

Abstract: Unbiased chemoproteomic profiling of small molecule interactions with endogenous proteins is important for drug discovery. For meaningful results, all protein classes have to be tractable, including G-protein coupled receptors (GPCRs). These are hardly tractable by affinity pulldown from lysates. We report a Capture Compound (CC)-based strategy to target and identify GPCRs directly from living cells. We synthesized CCs with sertindole attached to the CC scaffold in different orientations to target the dopamine D2 receptor (DRD2) heterologously expressed in HEK293 cells. The structure-activity relationship of sertindole for DRD2 binding is reflected in the activities of the sertindole CCs in radioligand displacement, cell-based assays, and CCMS. The activity pattern was rationalized by molecular modelling. The most active CC showed activities very similar to unmodifed sertindole. Well below 100 fmol of DRD2 in living cells used as experiment input were sufficient for unambiguous identification of captured DRD2 by mass spectrometry. Our new CCMS workflow broadens the arsenal of chemoproteomic technologies to close a critical gap for the comprehensive characterization of drug-protein interactions.

A Self-Assembled Oligopeptide as a Versatile NMR Alignment Medium for the Measurement of Residual Dipolar Couplings in Methanol
Lei(*), X. X., Qiu(*), F., Sun, H., Bai(*), L. W., Wang(*), W. X., Xiang(*), W. S.; Xiao(*), H. P.
Angew Chem Int Edit, 56:12857-12861
(2017)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Residual dipolar coupling (RDC) is a powerful structural parameter for the determination of the constitution, conformation, and configuration of organic molecules. Herein, we report the first liquid crystal-based orienting medium that is compatible with MeOH, thus enabling RDC acquisitions of a wide range of intermediate to polar organic molecules. The liquid crystals were produced from self-assembled oligopeptide nanotubes (AAKLVFF), which are stable at very low concentrations. The presented alignment medium is highly homogeneous, and the size of RDCs can be scaled with the concentration of the peptide. To assess the accuracy of the RDC measurement by employing this new medium, seven bioactive natural products from different classes were chosen and analyzed. The straightforward preparation of the anisotropic alignment sample will offer a versatile and robust protocol for the routine RDC measurement of natural products.

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.

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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 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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