FMP Publications

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

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References
Coumarin-based octopamine phototriggers and their effects on an insect octopamine receptor
Schaal, J., Dekowski, B., Wiesner, B., Eichhorst, J., Marter(*), K., Vargas(*), C., Keller(*), S., Eremina(*), N., Barth(*), A., Baumann(*), A., Eisenhardt(*), D.; Hagen, V.
Chembiochem, 13:1458-1464
(2012)

Tags: Synthetic Organic Biochemistry (Hagen), Cellular Imaging (Wiesner)

Abstract: We have developed and characterized efficient caged compounds of the neurotransmitter octopamine. For derivatization, we introduced [6-bromo-8-(diethylaminomethyl)-7-hydroxycoumarin-4-yl]methoxycarbonyl (DBHCMOC) and 6-bromo-7-hydroxy-8-[(piperazin-1-yl)methyl]coumarin-4-ylmethoxycarbonyl (PBHCMOC) moieties as novel photo-removable protecting groups. The caged compounds were functionally inactive when applied to heterologously expressed octopamine receptors (AmOctalpha1R). Upon irradiation with UV-visible or IR light, bioactive octopamine was released and evoked Ca2+ signals in AmOctalpha1R-expressing cells. The pronounced water solubility of compounds 2-4 in particular holds great promise for these substances as excellent phototriggers of this important neurotransmitter.

Membrane biology: fission behind BARs
Haucke, V.
Curr Biol, 22:R455-457
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Membrane bending is accomplished in part by amphipathic helix insertion into the bilayer and the assembly of BAR domain scaffolds preparing the membrane for fission. Two recent studies highlight the roles of amphipathic helices and BAR scaffolds in membrane fission and establish the structural basis of membrane bending by the N-BAR protein endophilin.

Spontaneous neurotransmission: a SNARE for the rest
Kononenko(*), N. L.; Haucke, V.
Neuron, 73:3-5
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: In addition to activity-dependent neurotransmission, neurons can undergo spontaneous activity-independent neurotransmitter release with low probability. In this issue of Neuron, Ramirez et al. (2012) now identify the noncanonical endosomal SNARE Vps10p-tail-interactor1a (Vti1a) as a regulator of spontaneously fusing vesicles.

Multi-colour direct STORM with red emitting carbocyanines
Lampe(*), A., Haucke, V., Sigrist(*), S. J., Heilemann(*), M.; Schmoranzer, J.
Biology of the cell, 104:229-237
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: BACKGROUND INFORMATION: Single molecule-based super-resolution methods have become important tools to study nanoscale structures in cell biology. However, the complexity of multi-colour applications has prevented them from being widely used amongst biologists. Direct stochastic optical reconstruction microscopy (dSTORM) offers a simple way to perform single molecule super-resolution imaging without the need for an activator fluorophore and compatible with many conventionally used fluorophores. The search for the ideal dye pairs suitable for dual-colour dSTORM has been compromised by the fact that fluorophores spectrally apt for dual-colour imaging differ with respect to the optimal buffer conditions required for photoswitching and the generation of prolonged non-fluorescent (OFF) states. RESULTS: We present a novel variant of dSTORM that combines advantages of spectral demixing with the buffer compatible blinking properties of red emitting carbocyanine dyes, spectral demixing dSTORM (SD-dSTORM). In contrast to previously published work, SD-dSTORM requires reduced laser power and fewer imaging frames for the faithful reconstruction of super-resolved biological nanostructures. In addition, SD-dSTORM allows the use of commercially available rather than custom-made probes and does not rely on potentially error-prone cross-talk correction, thus allowing reliable co-localisation. CONCLUSIONS: SD-dSTORM presents a significant advance towards user-friendly single molecule localisation-based super-resolution microscopy combining advantages of state-of-the-art methodologies to perform fast, reliable and efficient multi-colour dSTORM.

Turning CALM into excitement: AP180 and CALM in endocytosis and disease
Maritzen, T., Koo, S. J.; Haucke, V.
Biology of the cell, 104:588-602
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Dynamic flux of membrane between intracellular compartments is a key feature of all eukaryotic cells. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) play a crucial role in membrane dynamics by facilitating membrane fusion, for example at synapses where small synaptic vesicles (SVs) undergo activity-regulated neuroexocytosis, followed by the endocytic re-cycling of SV proteins and lipids. Recent work shows that the assembly protein 180 (AP180) N-terminal homology (ANTH) domain containing proteins AP180 and clathrin assembly lymphoid myeloid leukaemia (CALM) not only regulate the assembly of the endocytic machinery but also act as sorters for a subset of SNAREs, the vesicle-associated membrane proteins (VAMPs), most notably VAMP/synaptobrevin 2 at synapses. In this review, we summarise the current state of knowledge about the roles of AP180 and CALM family members in clathrin-dependent membrane traffic, the molecular mechanistic basis for their activities and their potential involvement in human disease.

Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex
Maritzen, T., Zech(*), T., Schmidt(*), M. R., Krause, E., Machesky(*), L. M.; Haucke, V.
Proc Natl Acad Sci U S A, 109:10382-10387
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Mass Spectrometry (Krause, E.)

Abstract: Regulation of actin dynamics is key to many cell physiological processes, ranging from protrusion formation and control of cell shape to cellular motility, endocytosis, and vesicle movement. The actin-related protein (ARP)2/3 complex is a major actin nucleator organizing branched filament networks in lamellipodial protrusions and during cell migration downstream of nucleation-promoting factors (NPFs). Although many NPFs have been characterized in detail, only few ARP2/3 inhibitors are known. Here, we identify the trans-Golgi network (TGN)/endosomally localized adaptor protein (AP)-1-associated adaptor protein Gadkin as a negative regulator of ARP2/3 function. Loss of Gadkin is associated with a partial redistribution of ARP2/3 to the plasma membrane and with increased cell spreading and migration, phenotypes that depend on the presence of a functional ARP2/3 complex. Gadkin directly binds to ARP2/3 via a conserved tryptophan-based acidic cluster motif reminiscent of ARP2/3-binding sequences of NPFs but fails to facilitate ARP2/3-mediated actin assembly. Consistent with an inhibitory role of Gadkin on ARP2/3 function, ARP2/3 is found on motile Gadkin-containing endosomal vesicles under migration-inhibiting conditions from where it relocalizes to the plasma membrane following activation of NPFs. Together with the observation that Gadkin-mediated inhibition of cell spreading requires its binding to ARP2/3, these data indicate that Gadkin is a negative regulator of ARP2/3 function present on intracellular membranes.

Phosphatidylinositol 4-kinase II alpha function at endosomes is regulated by the ubiquitin ligase Itch
Mössinger(*), J., Wieffer, M., Krause, E., Freund, C., Gerth, F., Krauss, M.; Haucke, V.
Embo Rep, 13:1087-1094
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Protein Engineering (Freund), Mass Spectrometry (Krause, E.)

Abstract: Phosphatidylinositol (PI) 4-phosphate (PI(4) P) and its metabolizing enzymes serve important functions in cell signalling and membrane traffic. PI 4-kinase type II alpha (PI4KII alpha) regulates Wnt signalling, endosomal sorting of signalling receptors, and promotes adaptor protein recruitment to endosomes and the trans-Golgi network. Here we identify the E3 ubiquitin ligase Itch as binding partner and regulator of PI4KII alpha function. Itch directly associates with and ubiquitinates PI4KII alpha, and both proteins colocalize on endosomes containing Wnt-activated frizzled 4 (Fz4) receptor. Depletion of PI4KII alpha or Itch regulates Wnt signalling with corresponding changes in Fz4 internalization and degradative sorting. These findings unravel a new molecular link between phosphoinositide-regulated endosomal membrane traffic, ubiquitin and the modulation of Wnt signalling.

The early steps of endocytosis: From cargo selection to membrane deformation
Rao(*), Y. J., Rückert(*), C., Saenger(*), W.; Haucke, V.
Eur J Cell Biol, 91:226-233
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Clathrin-mediated endocytosis mediates the internalization of signaling and nutrient receptors, ion channels and regulates the endocytic recycling of pre- and postsynaptic membrane proteins. During early stages endocytic adaptors recognize sorting signals within this diverse array of cargo proteins destined for internalization. Cargo sequestration is mechanistically coupled to membrane deformation, a process involving BAR domain proteins, resulting in the generation of endocytic intermediates that finally undergo dynamin-mediated fission. Here we summarize recent insights gathered from a combination of structural, biochemical, and cell biological studies that have revealed a remarkable complexity of the machinery for endocytic sorting and membrane deformation. (C) 2011 Elsevier GmbH. All rights reserved.

At the Crossroads of Chemistry and Cell Biology: Inhibiting Membrane Traffic by Small Molecules
von Kleist(*), L.; Haucke, V.
Traffic, 13:495-504
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Intracellular membrane traffic regulates cell physiology at multiple levels ranging from cell growth and development to the function of the nervous and immune systems. Multiple endocytic routes are used by distinct cargoes including ligands bound to their receptors but also viruses and pathogens to gain access to the cell interior. Within the endosomal system, proteins and lipids are sorted for degradation or recycling allowing cells to dynamically respond to environmental signals and to regulate cell shape and morphology. Some receptors or toxins are sorted along the retrograde pathway from endosomes to the Golgi complex, where they intersect with secretory cargo destined for exocytosis. Genetic manipulations of these pathways frequently cause problems with regard to data interpretation as the resulting phenotypes may be indirect consequences resulting from perturbation of multiple steps or trafficking routes. Hence, novel approaches are needed to acutely and reversibly perturb intracellular membrane traffic, e.g. by small molecule inhibitors. Such drugs may also be pharmacologically important as they offer new avenues to fight human diseases. Here, we provide an overview of the small molecules available to interfere with intracellular membrane traffic and outline strategies for future research.

Regulation of Phosphoinositide-Metabolizing Enzymes by Clathrin Coat Proteins
Wieffer(*), M., Haucke, V.; Krauss(*), M.
Method Cell Biol, 108:209-225
(2012)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Clathrin plays key roles in endocytic and endo-lysosomal membrane dynamics by facilitating the formation of coated vesicles at the plasma membrane and at the trans-Golgi network (TGN)/endosomal boundary. Assembly of the clathrin lattice critically depends on adaptor proteins and accessory proteins, which connect the clathrin scaffold to the membrane and to transmembrane cargo including receptors, transporters, channels, and SNARE proteins. The recruitment of adaptor proteins to membrane surfaces is triggered by coincidence-detection mechanisms involving phosphoinositides (PIs), cargo proteins, and in many cases small GTPases. To tightly regulate coat formation, there is extensive cross-talk between PI-metabolizing enzymes and adaptor proteins. One of the best studied examples is the endocytic clathrin adaptor complex AP-2, which binds plasma membrane-enriched PI(4,5)P-2. In neurons, PI(4,5)P2 is synthesized from PI(4)P primarily by the gamma-isoform of the type I phosphatidylinositol 4-phosphate 5-kinase family (PIPKI gamma), whose enzymatic activity is regulated by direct binding to, amongst others, the small GTPase Arf6 and AP-2. Cargo-bound AP-2 potently stimulates PIPK1 gamma activity and thereby drives AP-2-membrane interactions. This feed-forward loop is thought to facilitate membrane translocation of additional AP-2 molecules and concomitantly clathrin, but also of endocytic accessory proteins, many of which directly associate with PI(4,5)P2. It is likely that similar mechanisms support the formation of coated vesicles at the trans-Golgi network (TGN) and on endosomes, involving PI(4)P and PI(3)P respectively, but detailed knowledge is lacking to date. To explore how coat proteins regulate kinase activity, assays are needed to sensitively detect subtle changes in PI synthesis and to discriminate between the various PI species. Here we describe a sensitive and specific radioactivity-based assay to measure PI kinase activity.

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