FMP Publications

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

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Autophagosome Formation by Endophilin Keeps Synapses in Shape
Kuijpers, M.; Haucke, V.
Neuron, 92:675-677

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Soukup et al. (2016), in this issue of Neuron, and Murdoch et al. (2016), in Cell Reports, reveal an unexpected function for the endocytic protein endophilin in autophagosome formation at synapses: preventing neurodegeneration and ataxia.

Tyrosine-phosphorylation of the scaffold protein ADAP and its role in T cell signaling
Kuropka, B., Schraven(*), B., Kliche(*), S., Krause, E.; Freund(*), C.
Expert Rev Proteomics, 13:545-554

Tags: Mass Spectrometry (Krause, E.)

Abstract: INTRODUCTION: The Adhesion and Degranulation promoting Adaptor Protein (ADAP) is phosphorylated upon T cell activation and acts as a scaffold for the formation of a signaling complex that integrates molecular interactions between T cell or chemokine receptors, the actin cytoskeleton, and integrin-mediated cellular adhesion and migration. AREAS COVERED: This article reviews current knowledge of the functions of the adapter protein ADAP in T cell signaling with a focus on the role of individual phosphotyrosine (pY) motifs for SH2 domain mediated interactions. The data presented was obtained from literature searches (PubMed) as well as the authors own research on the topic. Expert commentary: ADAP can be regarded as a paradigmatic example of how tyrosine phosphorylation sites serve as dynamic interaction hubs. Molecular crowding at unstructured and redundant sites (pY595, pY651) is contrasted by more specific interactions enabled by the three-dimensional environment of a particular phosphotyrosine motif (pY571).

Structural analysis of a signal peptide inside the ribosome tunnel by DNP MAS NMR
Lange, S., Franks, W. T., Rajagopalan(*), N., Döring(*), K., Geiger, M. A., Linden, A., van Rossum, B. J., Kramer(*), G., Bukau(*), B.; Oschkinat, H.
Sci Adv, 2:e1600379

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

Abstract: Proteins are synthesized in cells by ribosomes and, in parallel, prepared for folding or targeting. While ribosomal protein synthesis is progressing, the nascent chain exposes amino-terminal signal sequences or transmembrane domains that mediate interactions with specific interaction partners, such as the signal recognition particle (SRP), the SecA-adenosine triphosphatase, or the trigger factor. These binding events can set the course for folding in the cytoplasm and translocation across or insertion into membranes. A distinction of the respective pathways depends largely on the hydrophobicity of the recognition sequence. Hydrophobic transmembrane domains stabilize SRP binding, whereas less hydrophobic signal sequences, typical for periplasmic and outer membrane proteins, stimulate SecA binding and disfavor SRP interactions. In this context, the formation of helical structures of signal peptides within the ribosome was considered to be an important factor. We applied dynamic nuclear polarization magic-angle spinning nuclear magnetic resonance to investigate the conformational states of the disulfide oxidoreductase A (DsbA) signal peptide stalled within the exit tunnel of the ribosome. Our results suggest that the nascent chain comprising the DsbA signal sequence adopts an extended structure in the ribosome with only minor populations of helical structure.

Novel organic dyes for multicolor localization-based super-resolution microscopy
Lehmann, M., Lichtner, G., Klenz, H.; Schmoranzer, J.
J Biophotonics, 9:161-170

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Precise multicolor single molecule localization-based microscopy (SMLM) requires bright probes with compatible photo-chemical and spectral properties to resolve distinct molecular species at the nanoscale. The accuracy of multicolor SMLM is further challenged by color channel crosstalk and chromatic alignment errors. These constrains limit the applicability of known reversibly switchable organic dyes for optimized multicolor SMLM. Here, we tested 28 commercially available dyes for their suitability to super-resolve a known cellular nanostructure. We identified eight novel dyes in different spectral regimes that enable high quality dSTORM imaging. Among those, the spectrally close dyes CF647 and CF680 comprise an optimal dye pair for spectral demixing-based, registration free multicolor dSTORM with low crosstalk. Combining this dye pair with the separately excited CF568 we performed 3-color dSTORM to image the relative nanoscale distribution of components of the endocytic machinery and the cytoskeleton.

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

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.

Differentially Isotope-Labeled Nucleosomes To Study Asymmetric Histone Modification Crosstalk by Time-Resolved NMR Spectroscopy
Liokatis, S., Klingberg, R., Tan(*), S.; Schwarzer(*), D.
Angew Chem Int Ed Engl, 55:8262-8265

Tags: In-Cell NMR (Selenko), Protein Chemistry (Schwarzer)

Abstract: Post-translational modifications (PTMs) of histones regulate chromatin structure and function. Because nucleosomes contain two copies each of the four core histones, the establishment of different PTMs on individual "sister" histones in the same nucleosomal context, that is, asymmetric histone PTMs, are difficult to analyze. Here, we generated differentially isotope-labeled nucleosomes to study asymmetric histone modification crosstalk by time-resolved NMR spectroscopy. Specifically, we present mechanistic insights into nucleosomal histone H3 modification reactions in cis and in trans, that is, within individual H3 copies or between them. We validated our approach by using the H3S10phK14ac crosstalk mechanism, which is mediated by the Gcn5 acetyltransferase. Moreover, phosphorylation assays on methylated substrates showed that, under certain conditions, Haspin kinase is able to produce nucleosomes decorated asymmetrically with two distinct types of PTMs.

The Use of a Combination of RDC and Chiroptical Spectroscopy for Determination of the Absolute Configuration of Fusariumin A from the Fungus Fusarium sp
Liu(*), L. Y., Sun, H., Griesinger(*), C.; Liu(*), J. K.
Natural products and bioprospecting, 6:41-48

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: A new alkylpyrrole derivative, fusariumin A (1), was isolated from the culture broth of the fungus Fusarium sp. The absolute configuration of fuasiumin A has been established as (2'R,3'R) using a combination of RDC (residual dipolar coupling)-based NMR and DFT-supported chiroptical spectroscopy. It is worth to note that in this study without the aid of the RDC analysis, an unambiguous determination of configuration and conformation was not feasible due to the excessive conformational possibilities of this open-chain compound.

Quantitative and Qualitative Analysis of Surface Modified Cellulose Utilizing TGA-MS
Loof(*), D., Hiller, M., Oschkinat, H.; Koschek(*), K.
Materials (Basel, Switzerland), 9

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: With the aim to enhance interfacial adhesion of a hydrophobic polymer matrix and cellulosic fibers and fillers, chemical surface modifications with silane coupling agents are performed. Thermogravimetric analysis (TGA) could be used to determine the degree of surface functionalization. However, similar thermal properties of treated and untreated cellulose hamper a precise determination of silane loading. This contribution deals with quantitative determination of silane loading combining both TGA and elemental analysis. Firstly, silane modified celluloses were studied by FT-IR, Raman, solid state NMR spectroscopy, and polarized light microscopy in order to determine functional groups and to study the impact of chemical treatment on cellulose morphology. Secondly, thermal stability and pyrolysis processes were studied by TG-MS analysis. In order to determine the exact silane loading, the mass percentages of the appropriate elements were quantified by elemental analysis and correlated with the charred residues determined by TGA yielding a linear dependency. With that correlation, it was possible to determine silane loadings for additional samples utilizing simple TGA measurements. The main advantage of that approach is that only one calibration is necessary for routine analyses of further samples and TGA-MS coupling gives additional information on thermal stability and pyrolysis routes, simultaneously.

Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
Lopes da Silva(*), M., O'Connor(*), M. N., Kriston-Vizi(*), J., White(*), I. J., Al-Shawi(*), R., Simons(*), J. P., Mössinger, J., Haucke, V.; Cutler(*), D. F.
J Cell Sci, 129:2096-2105

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIalpha and PI4KIIbeta in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIalpha-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function.

Phosphatidylinositol 3-phosphates-at the interface between cell signalling and membrane traffic
Marat, A. L.; Haucke, V.
EMBO J, 35:561-579

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Phosphoinositides (PIs) form a minor class of phospholipids with crucial functions in cell physiology, ranging from cell signalling and motility to a role as signposts of compartmental membrane identity. Phosphatidylinositol 3-phosphates are present at the plasma membrane and within the endolysosomal system, where they serve as key regulators of both cell signalling and of intracellular membrane traffic. Here, we provide an overview of the metabolic pathways that regulate cellular synthesis of PI 3-phosphates at distinct intracellular sites and discuss the mechanisms by which these lipids regulate cell signalling and membrane traffic. Finally, we provide a framework for how PI 3-phosphate metabolism is integrated into the cellular network.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
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