FMP Publications

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

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References

2017

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
Rathjen(*), T., Yan(*), X., Kononenko, N. L., Ku(*), M. C., Song(*), K., Ferrarese(*), L., Tarallo(*), V., Puchkov, D., Kochlamazashvili, G., Brachs(*), S., Varela(*), L., Szigeti-Buck(*), K., Yi(*), C. X., Schriever(*), S. C., Tattikota(*), S. G., Carlo(*), A. S., Moroni(*), M., Siemens(*), J., Heuser(*), A., van der Weyden(*), L., Birkenfeld(*), A. L., Niendorf(*), T., Poulet(*), J. F. A., Horvath(*), T. L., Tschop(*), M. H., Heinig(*), M., Trajkovski(*), M., Haucke, V.; Poy(*), M. N.
Nat Neurosci,
(2017)

Tags: Molecular Pharmacology and Cell Biology (Haucke), Cellular Imaging (Wiesner, Puchkov)

Abstract: Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.

Lipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission
Schöneberg(*), J., Lehmann, M., Ullrich(*), A., Posor, Y., Lo, W. T., Lichtner, G., Schmoranzer, J., Haucke, V.; Noe(*), F.
Nat Commun, 8:15873
(2017)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Clathrin-mediated endocytosis (CME) involves membrane-associated scaffolds of the bin-amphiphysin-rvs (BAR) domain protein family as well as the GTPase dynamin, and is accompanied and perhaps triggered by changes in local lipid composition. How protein recruitment, scaffold assembly and membrane deformation is spatiotemporally controlled and coupled to fission is poorly understood. We show by computational modelling and super-resolution imaging that phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] synthesis within the clathrin-coated area of endocytic intermediates triggers selective recruitment of the PX-BAR domain protein SNX9, as a result of complex interactions of endocytic proteins competing for phospholipids. The specific architecture induces positioning of SNX9 at the invagination neck where its self-assembly regulates membrane constriction, thereby providing a template for dynamin fission. These data explain how lipid conversion at endocytic pits couples local membrane constriction to fission. Our work demonstrates how computational modelling and super-resolution imaging can be combined to unravel function and mechanisms of complex cellular processes.

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.

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.

Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells
Appelt-Menzel(*), A., Cubukova(*), A., Günther(*), K., Edenhofer(*), F., Piontek(*), J., Krause, G., Stüber(*), T., Walles(*), H., Neuhaus(*), W.; Metzger(*), M.
Stem cell reports, 8:894-906
(2017)

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

Abstract: In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Omega cm2 and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.

NMR Hyperpolarization Techniques of Gases
Barskiy(*), D. A., Coffey(*), A. M., Nikolaou(*), P., Mikhaylov(*), D. M., Goodson(*), B. M., Branca(*), R. T., Lu(*), G. J., Shapiro(*), M. G., Telkki(*), V. V., Zhivonitko(*), V. V., Koptyug(*), I. V., Salnikov(*), O. G., Kovtunov(*), K. V., Bukhtiyarov(*), V. I., Rosen(*), M. S., Barlow(*), M. J., Safavi(*), S., Hall(*), I. P., Schroeder, L.; Chekmenev(*), E. Y.
Chemistry, 23:725-751
(2017)

Tags: Molecular Imaging (Schröder)

Abstract: Nuclear spin polarization can be significantly increased through the process of hyperpolarization, leading to an increase in the sensitivity of nuclear magnetic resonance (NMR) experiments by 4-8 orders of magnitude. Hyperpolarized gases, unlike liquids and solids, can often be readily separated and purified from the compounds used to mediate the hyperpolarization processes. These pure hyperpolarized gases enabled many novel MRI applications including the visualization of void spaces, imaging of lung function, and remote detection. Additionally, hyperpolarized gases can be dissolved in liquids and can be used as sensitive molecular probes and reporters. This Minireview covers the fundamentals of the preparation of hyperpolarized gases and focuses on selected applications of interest to biomedicine and materials science.

Claudins are essential for cell shape changes and convergent extension movements during neural tube closure
Baumholtz(*), A. I., Simard(*), A., Nikolopoulou(*), E., Oosenbrug(*), M., Collins(*), M. M., Piontek, A., Krause, G., Piontek(*), J., Greene(*), N. D. E.; Ryan(*), A. K.
Developmental biology, 428:25-38
(2017)

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

Abstract: During neural tube closure, regulated changes at the level of individual cells are translated into large-scale morphogenetic movements to facilitate conversion of the flat neural plate into a closed tube. Throughout this process, the integrity of the neural epithelium is maintained via cell interactions through intercellular junctions, including apical tight junctions. Members of the claudin family of tight junction proteins regulate paracellular permeability, apical-basal cell polarity and link the tight junction to the actin cytoskeleton. Here, we show that claudins are essential for neural tube closure: the simultaneous removal of Cldn3, -4 and -8 from tight junctions caused folate-resistant open neural tube defects. Their removal did not affect cell type differentiation, neural ectoderm patterning nor overall apical-basal polarity. However, apical accumulation of Vangl2, RhoA, and pMLC were reduced, and Par3 and Cdc42 were mislocalized at the apical cell surface. Our data showed that claudins act upstream of planar cell polarity and RhoA/ROCK signaling to regulate cell intercalation and actin-myosin contraction, which are required for convergent extension and apical constriction during neural tube closure, respectively.

Complete NMR assignment and conformational analysis of 17-alpha-ethinylestradiol by using RDCs obtained in grafted graphene oxide
Franca(*), J. A., Navarro-Vazquez(*), A., Lei(*), X., Sun, H., Griesinger(*), C.; Hallwass(*), F.
Magn Reson Chem, 55:297-303
(2017)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: The 1 H and 13 C NMR spectra of 17-alpha-ethinylestradiol (EE2), a well-known contraceptive, including diastereotopic methylene groups, were fully assigned with the help of residual dipolar couplings (RDC) measured in the recently developed grafted graphene oxide orienting medium. RDC analysis, which included all 1 DCH couplings and the long-range 2 DCH1 H-C identical with13 C coupling, also pointed to the presence of a minor conformation arising from pseudo-rotation of the steroid B ring. Saturation-transfer difference (STD) measurements revealed that the most likely interaction between EE2 and orienting medium occurred on the C and D ring. Copyright (c) 2016 John Wiley & Sons, Ltd.

Intersectin associates with synapsin and regulates its nanoscale localization and function
Gerth(*), F., Jäpel, M., Pechstein, A., Kochlamazashvili, G., Lehmann, M., Puchkov, D., Onofri(*), F., Benfenati(*), F., Nikonenko(*), A. G., Maritzen, T., Freund(*), C.; Haucke, V.
Proc Natl Acad Sci U S A, 114:12057-12062
(2017)

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

Abstract: Neurotransmission is mediated by the exocytic release of neurotransmitters from readily releasable synaptic vesicles (SVs) at the active zone. To sustain neurotransmission during periods of elevated activity, release-ready vesicles need to be replenished from the reserve pool of SVs. The SV-associated synapsins are crucial for maintaining this reserve pool and regulate the mobilization of reserve pool SVs. How replenishment of release-ready SVs from the reserve pool is regulated and which other factors cooperate with synapsins in this process is unknown. Here we identify the endocytic multidomain scaffold protein intersectin as an important regulator of SV replenishment at hippocampal synapses. We found that intersectin directly associates with synapsin I through its Src-homology 3 A domain, and this association is regulated by an intramolecular switch within intersectin 1. Deletion of intersectin 1/2 in mice alters the presynaptic nanoscale distribution of synapsin I and causes defects in sustained neurotransmission due to defective SV replenishment. These phenotypes were rescued by wild-type intersectin 1 but not by a locked mutant of intersectin 1. Our data reveal intersectin as an autoinhibited scaffold that serves as a molecular linker between the synapsin-dependent reserve pool and the presynaptic endocytosis machinery.

Molecular features of the L-type amino acid transporter 2 determine different import and export profiles for thyroid hormones and amino acids
Hinz, K. M., Neef, D., Rutz, C., Furkert, J., Köhrle(*), J., Schülein, R.; Krause, G.
Mol Cell Endocrinol, 443:163-174
(2017)

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

Abstract: The L-type amino acid transporter 2 (LAT2) imports amino acids (AA) and also certain thyroid hormones (TH), e.g. 3,3'-T2 and T3, but not rT3 and T4. We utilized LAT2 mutations (Y130A, N133S, F242W) that increase 3,3'-T2 import and focus here on import and export capacity for AA, T4, T3, BCH and derivatives thereof to delineate molecular features. Transport studies and analysis of competitive inhibition of import by radiolabelled TH and AA were performed in Xenopus laevis oocytes. Only Y130A, a pocket widening mutation, enabled import for T4 and increased it for T3. Mutant F242W showed increased 3,3'-T2 import but no import rates for other TH derivatives. No export was detected for any TH by LAT2-wild type (WT). Mutations Y130A and N133S enabled only the export of 3,3'-T2, while N133S also increased AA export. Thus, distinct molecular LAT2-features determine bidirectional AA transport but only an unidirectional 3,3'-T2 and T3 import.

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