FMP Publications

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

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References
A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels
Schewe(*), M., Nematian-Ardestani(*), E., Sun, H., Musinszki(*), M., Cordeiro(*), S., Bucci(*), G., de Groot(*), B. L., Tucker(*), S. J., Rapedius(*), M.; Baukrowitz(*), T.
Cell, 164:937-949
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Two-pore domain (K2P) K(+) channels are major regulators of excitability that endow cells with an outwardly rectifying background "leak" conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way "check valve" within the filter because outward movement of K(+) induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K(+)-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface
Seifert(*), W., Posor, Y., Schu(*), P., Stenbeck(*), G., Mundlos(*), S., Klaassen(*), S., Nürnberg(*), P., Haucke, V., Kornak(*), U.; Kühnisch(*), J.
Hum Mol Genet, 25:3836-3848
(2016)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked to familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), mental retardation, deafness and ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome-like puncta. Consistent with its subcellular localization, loss of ANK results in reduced formation of tubular membrane carriers from the TGN, perinuclear accumulation of early endosomes and impaired transferrin endocytosis. Our data indicate that clathrin/AP-mediated cycling of ANK between the TGN, endosomes, and the cell surface regulates membrane traffic at the TGN/endosomal interface. These findings suggest that dysfunction of Golgi-endosomal membrane traffic may contribute to ANKH-associated pathologies.

Dynamic Nuclear Polarization Provides New Insights into Chromophore Structure in Phytochrome Photoreceptors
Stöppler, D., Song(*), C., van Rossum, B. J., Geiger, M. A., Lang(*), C., Mroginski(*), M. A., Jagtap(*), A. P., Sigurdsson(*), S. T., Matysik(*), J., Hughes(*), J.; Oschkinat, H.
Angew Chem Int Ed Engl, 55:16017-16020
(2016)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Phytochromes are red/far-red photochromic photoreceptors acting as master regulators of development in higher plants, thereby controlling transcription of about 20 % of their genes. Light-induced isomerization of the bilin chromophore leads to large rearrangements in protein structure, whereby the role of protonation dynamics and charge distribution is of particular interest. To help unravel the inherent mechanisms, we present two-dimensional dynamic nuclear polarization (DNP) enhanced solid-state magic-angle spinning (MAS) NMR spectra of the functional sensory module of the cyanobacterial phytochrome Cph1. To this end, the pyrrole ring nitrogen signals were assigned unequivocally, enabling us to locate the positive charge of the phycocyanobilin (PCB) chromophore. To help analyze proton exchange pathways, the proximity of PCB ring nitrogen atoms and functionally relevant H2 O molecules was also determined. Our study demonstrates the value of DNP in biological solid-state MAS NMR spectroscopy.

Lipopeptide-based micellar and liposomal carriers: Influence of surface charge and particle size on cellular uptake into blood brain barrier cells
Sydow, K., Nikolenko, H., Lorenz, D., Müller(*), R. H.; Dathe, M.
Eur J Pharm Biopharm, 109:130-139
(2016)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Lipopeptide-based micelles and liposomes were found to differ in cell recognition and uptake mode into blood brain barrier (BBB) endothelial cells. Here we analyse the role of size and surface charge of micelles and liposomes composed of different lipopeptide sequences with respect to uptake into human brain capillary (HBMEC) and aortic (HAoEC) endothelial cells. Comparable to the dipalmitoylated apolipoprotein E-derived P2A2, lipopeptides of cationic poly-arginine (P2Rn), poly-lysine (P2Kn) and an anionic glutamic-acid sequence (P2En) self assemble into micelles (12-14nm in diameter) with high surface charge density, and bind to small (SUVs, about 24nm in diameter) and large (LUV, about 100nm in diameter) liposomes at variable lipid to peptide ratios. The interaction pattern of the resulting particles with endothelial cells is highly variable as revealed by confocal laser scanning microscopic (CLSM) and fluorescence assisted cell sorting (FACS) studies. Micelles and SUVs with high P2A2 density are efficiently and selectively internalized into HBMEC. P2Kn micelles strongly accumulate in both the cytosol and at the cell membrane, while the interaction of liposomes tagged with a low amount of P2A2 and P2Kn with the cells was reduced. Anionic micelles seem to dissociate in the presence of cells and P2En molecules incorporate into the cellular membrane whereas the negatively charged liposomes hardly interact with cells. Surprisingly, all poly-R-based particles show high selectivity for HBMEC compared to HAoEC, independent of particle size and peptide surface density. The P2Rn-mediated internalization is highly efficient and partially clathrin-dependent. The oligo-R lipopeptide is considered to be most promising to selectively transport different drug carriers into the blood brain barrier.

Structural disorder of monomeric alpha-synuclein persists in mammalian cells
Theillet, F. X., Binolfi, A., Bekei, B., Martorana(*), A., Rose, H. M., Stuiver, M., Verzini, S., Lorenz, D., van Rossum, M., Goldfarb(*), D.; Selenko, P.
Nature, 530:45-50
(2016)

Tags: In-Cell NMR (Selenko), Cellular Imaging (Wiesner)

Abstract: Intracellular aggregation of the human amyloid protein alpha-synuclein is causally linked to Parkinson's disease. While the isolated protein is intrinsically disordered, its native structure in mammalian cells is not known. Here we use nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of alpha-synuclein in different mammalian cell types. We show that the disordered nature of monomeric alpha-synuclein is stably preserved in non-neuronal and neuronal cells. Under physiological cell conditions, alpha-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-beta component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. These results establish that different types of crowded intracellular environments do not inherently promote alpha-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells.

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