FMP Publications

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

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References
Safeguards of Neurotransmission: Endocytic Adaptors as Regulators of Synaptic Vesicle Composition and Function
Kaempf, N.; Maritzen, T.
Front Cell Neurosci, 11:320
(2017)

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

Abstract: Communication between neurons relies on neurotransmitters which are released from synaptic vesicles (SVs) upon Ca2+ stimuli. To efficiently load neurotransmitters, sense the rise in intracellular Ca2+ and fuse with the presynaptic membrane, SVs need to be equipped with a stringently controlled set of transmembrane proteins. In fact, changes in SV protein composition quickly compromise neurotransmission and most prominently give rise to epileptic seizures. During exocytosis SVs fully collapse into the presynaptic membrane and consequently have to be replenished to sustain neurotransmission. Therefore, surface-stranded SV proteins have to be efficiently retrieved post-fusion to be used for the generation of a new set of fully functional SVs, a process in which dedicated endocytic sorting adaptors play a crucial role. The question of how the precise reformation of SVs is achieved is intimately linked to how SV membranes are retrieved. For a long time both processes were believed to be two sides of the same coin since Clathrin-mediated endocytosis (CME), the proposed predominant SV recycling mode, will jointly retrieve SV membranes and proteins. However, with the recent proposal of Clathrin-independent SV recycling pathways SV membrane retrieval and SV reformation turn into separable events. This review highlights the progress made in unraveling the molecular mechanisms mediating the high-fidelity retrieval of SV proteins and discusses how the gathered knowledge about SV protein recycling fits in with the new notions of SV membrane endocytosis.

In vivo properties of the disaggregase function of J-proteins and Hsc70 in Caenorhabditis elegans stress and aging
Kirstein, J., Arnsburg, K., Scior, A., Szlachcic(*), A., Guilbride(*), D. L., Morimoto(*), R. I., Bukau(*), B.; Nillegoda(*), N. B.
Aging cell,
(2017)

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: Protein aggregation is enhanced upon exposure to various stress conditions and aging, which suggests that the quality control machinery regulating protein homeostasis could exhibit varied capacities in different stages of organismal lifespan. Recently, an efficient metazoan disaggregase activity was identified in vitro, which requires the Hsp70 chaperone and Hsp110 nucleotide exchange factor, together with single or cooperating J-protein co-chaperones of classes A and B. Here, we describe how the orthologous Hsp70s and J-protein of Caenorhabditis elegans work together to resolve protein aggregates both in vivo and in vitro to benefit organismal health. Using an RNAi knockdown approach, we show that class A and B J-proteins cooperate to form an interactive flexible network that relocalizes to protein aggregates upon heat shock and preferentially recruits constitutive Hsc70 to disaggregate heat-induced protein aggregates and polyQ aggregates that form in an age-dependent manner. Cooperation between class A and B J-proteins is also required for organismal health and promotes thermotolerance, maintenance of fecundity, and extended viability after heat stress. This disaggregase function of J-proteins and Hsc70 therefore constitutes a powerful regulatory network that is key to Hsc70-based protein quality control mechanisms in metazoa with a central role in the clearance of aggregates, stress recovery, and organismal fitness in aging.

Disruption of the vacuolar-type H+-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes
Kissing(*), S., Rudnik(*), S., Damme(*), M., Lullmann-Rauch(*), R., Ichihara*), A., Kornak(*), U., Eskelinen(*), E. L., Jabs, S., Heeren(*), J., De Brabander(*), J. K., Haas(*), A.; Saftig(*), P.
Autophagy, 13:670-685
(2017)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: The vacuolar-type H+-translocating ATPase (v-H+-ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H+-ATPase and MTORC1, we destablilized v-H+-ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes. This cellular phenotype was not caused by a block in endocytic maturation or an impaired acidification. However, the degradation of LC3-II in the knockout hepatocytes appeared to be reduced. When v-H+-ATPase levels were decreased, we observed lysosome association of MTOR and normal signaling of MTORC1 despite an increase in autophagic marker proteins. To better understand why MTORC1 can be active when v-H+-ATPase is depleted, the activation of MTORC1 was analyzed in ATP6AP2-deficient fibroblasts. In these cells, very little amino acid-elicited activation of MTORC1 was observed. In contrast, insulin did induce MTORC1 activation, which still required intracellular amino acid stores. These results suggest that in vivo the regulation of macroautophagy depends not only on v-H+-ATPase-mediated regulation of MTORC1.

Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work
Kleinau(*), G., Worth, C. L., Kreuchwig, A., Biebermann(*), H., Marcinkowski, P., Scheerer(*), P.; Krause, G.
Front Endocrinol (Lausanne), 8:86
(2017)

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

Abstract: The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration
Kononenko, N. L., Claßen, G. A., Kuijpers, M., Puchkov, D., Maritzen, T., Tempes(*), A., Malik(*), A. R., Skalecka(*), A., Bera(*), S., Jaworski(*), J.; Haucke, V.
Nat Commun, 8:14819
(2017)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Membrane Traffic and Cell Motility (Maritzen), Cellular Imaging (Wiesner, Puchkov)

Abstract: Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins. In neurons, autophagosomes form in distal axons and are trafficked retrogradely to fuse with lysosomes in the soma. Although defective neuronal autophagy is associated with neurodegeneration, the function of neuronal autophagosomes remains incompletely understood. We show that in neurons, autophagosomes promote neuronal complexity and prevent neurodegeneration in vivo via retrograde transport of brain-derived neurotrophic factor (BDNF)-activated TrkB receptors. p150Glued/dynactin-dependent transport of TrkB-containing autophagosomes requires their association with the endocytic adaptor AP-2, an essential protein complex previously thought to function exclusively in clathrin-mediated endocytosis. These data highlight a novel non-canonical function of AP-2 in retrograde transport of BDNF/TrkB-containing autophagosomes in neurons and reveal a causative link between autophagy and BDNF/TrkB signalling.

Reconciling the different faces of hippocampal theta: the role of theta oscillations in cognitive, emotional and innate behaviors
Korotkova, T., Ponomarenko, A., Monaghan(*), C. K., Poulter(*), S. L., Cacucci(*), F., Wills(*), T., Hasselmo(*), M. E.; Lever(*), C.
Neuroscience and biobehavioral reviews,
(2017)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: The theta oscillation (5-10Hz) is a prominent behavior-specific brain rhythm. This review summarizes studies showing the multifaceted role of theta rhythm in cognitive functions, including spatial coding, time coding and memory, exploratory locomotion and anxiety-related behaviors. We describe how activity of hippocampal theta rhythm generators - medial septum, nucleus incertus and entorhinal cortex, links theta with specific behaviors. We review evidence for functions of the theta-rhythmic signaling to subcortical targets, including lateral septum. Further, we describe functional associations of theta oscillation properties - phase, frequency and amplitude - with memory, locomotion and anxiety, and outline how manipulations of these features, using optogenetics or pharmacology, affect associative and innate behaviors. We discuss work linking cognition to the slope of the theta frequency to running speed regression, and emotion-sensitivity (anxiolysis) to its y-intercept. Finally, we describe parallel emergence of theta oscillations, theta-mediated neuronal activity and behaviors during development. This review highlights a complex interplay of neuronal circuits and synchronization features, which enables an adaptive regulation of multiple behaviors by theta-rhythmic signaling.

Thyroid hormone transport across L-type amino acid transporters: What can molecular modelling tell us?
Krause, G.; Hinz, K. M.
Mol Cell Endocrinol,
(2017)

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

Abstract: Thyroid hormones (THs) and their derivatives require transmembrane transporters (TTs) to mediate their translocation across the cell membrane. Among these TTs, the L-type amino acid transporters (LAT) not only transport amino acids (AAs) but also certain THs and their derivatives. This review summarizes available knowledge concerning structure function patterns of the TH transport by LAT1 and LAT2. For example, LAT2 imports 3,3'-T2 and T3, but not rT3 and T4. In contrast to amino acids, THs are not at all exported by LAT2. Homology modelling of LAT1 and LAT2 is based on available crystal structures from the same superfamily the amino acid/polyamine/organocation transporter (APC). Molecular model guided mutagenesis has been used to predict substrate interaction sites. A common recognition feature for amino acid- and TH-derivatives has been suggested in an interior cavity of LAT1 and LAT2. Therein additional distinct molecular determinants that are responsible for the bidirectional AA transport but allowing only unidirectional import of particular THs have been confirmed for LAT2 by mutagenesis. Characterized substrate features that are needed for TH translocation and distinct LAT2 properties will be highlighted to understand the molecular import and export mechanisms of this transporter in more detail.

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.

Multivalent Peptide-Nanoparticle Conjugates for Influenza-Virus Inhibition
Lauster(*), D., Glanz, M., Bardua(*), M., Ludwig(*), K., Hellmund(*), M., Hoffmann(*), U., Hamann(*), A., Böttcher(*), C., Haag(*), R., Hackenberger, C. P. R.; Herrmann(*), A.
Angew Chem Int Ed Engl, 56:5931-5936
(2017)

Tags: Chemical Biology II (Hackenberger)

Abstract: To inhibit binding of the influenza A virus to the host cell glycocalyx, we generate multivalent peptide-polymer nanoparticles binding with nanomolar affinity to the virus via its spike protein hemagglutinin. The chosen dendritic polyglycerol scaffolds are highly biocompatible and well suited for a multivalent presentation. We could demonstrate in vitro that by increasing the size of the polymer scaffold and adjusting the peptide density, viral infection is drastically reduced. Such a peptide-polymer conjugate qualified also in an in vivo infection scenario. With this study we introduce the first non-carbohydrate-based, covalently linked, multivalent virus inhibitor in the nano- to picomolar range by ensuring low peptide-ligand density on a larger dendritic scaffold.

Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging
Lechler(*), M. C., Crawford(*), E. D., Groh(*), N., Widmaier(*), K., Jung(*), R., Kirstein, J., Trinidad(*), J. C., Burlingame(*), A. L.; David(*), D. C.
Cell Rep, 18:454-467
(2017)

Tags: Proteostasis in Aging and Disease (Kirstein)

Abstract: Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1) is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule-related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases.

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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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