FMP Publications

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

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References
Efficient alpha-helix induction in a linear peptide chain by N-capping with a bridged-tricyclic diproline analogue
Hack(*), V., Reuter(*), C., Opitz, R., Schmieder, P., Beyermann, M., Neudörfl(*), J. M., Kühne, R.; Schmalz(*), H. G.
Angew Chem Int Ed Engl, 52:9539-9543
(2013)

Tags: Solution NMR (Schmieder), Peptide Synthesis (Beyermann), Computational Chemistry/Drug Design (Kühne)

Different intra- and intermolecular activation mechanisms at the human lutropin receptor: Lutropin induces only cis- and choriogonadotropin also trans-activation
Grzesik, P., Teichmann, A., Furkert, J., Rutz, C., Wiesner, B., Kleinau(*), G., Schülein, R., Gromoll(*), J.; Krause, G.
Exp Clin Endocr Diab, 121
(2013)

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

Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists
Hoyer, I., Haas, A. K., Kreuchwig, A., Schülein, R.; Krause, G.
Biochem Soc Trans, 41:213-217
(2013)

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

Abstract: The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.

Extended and structurally supported insights into extracellular mechanisms of the thyrotropin receptor
Krause, G., Kreuchwig, A.; Kleinau(*), G.
Exp Clin Endocr Diab, 121
(2013)

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

Research Resource: Novel Structural Insights Bridge Gaps in Glycoprotein Hormone Receptor Analyses
Kreuchwig, A., Kleinau(*), G.; Krause, G.
Mol Endocrinol, 27:1357-1363
(2013)

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

Abstract: The first version of a glycoprotein hormone receptor (GPHR) information resource was designed to link functional with structural GPHR information, in order to support sequence-structure-function analysis of the LH, FSH, and TSH receptors (http://ssfa-gphr.de). However, structural information on a binding- and signaling-sensitive extracellular fragment (similar to 100 residues), the hinge region, had been lacking. A new FSHR crystal structure of the hormone-bound extracellular domain has recently been solved. The structure comprises the leucine-rich repeat domain and most parts of the hinge region. We have not only integrated the new FSHR/FSH structure and the derived homology models of TSHR/TSH, LHCGR/CG, and LHCGR/LH into our web-based information resource, but have additionally provided novel tools to analyze the advanced structural features, with the common characteristics and distinctions between GPHRs, in a more precise manner. The hinge region with its second hormone-binding site allows us to assign functional data to the new structural features between hormone and receptor, such as binding details of a sulfated tyrosine (conserved throughout the GPHRs) extending into a pocket of the hormone. We have also implemented a protein interface analysis tool that enables the identification and visualization of extracellular contact points between interaction partners. This provides a starting point for comparing the binding patterns of GPHRs. Together with the mutagenesis data stored in the database, this will help to decipher the essential residues for ligand recognition and the molecular mechanisms of signal transduction, extending from the extracellular hormone-binding site toward the intracellular G protein-binding sites.

Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions
Schäfer(*), G., Milic(*), J., Eldahshan, A., Götz(*), F., Zühlke(*), K., Schillinger, C., Kreuchwig, A., Elkins(*), J. M., Abdul Azeez(*), K. R., Oder(*), A., Moutty(*), M. C., Masada(*), N., Beerbaum, M., Schlegel, B., Niquet(*), S., Schmieder, P., Krause, G., von Kries, J. P., Cooper(*), D. M., Knapp(*), S., Rademann, J., Rosenthal(*), W.; Klussmann(*), E.
Angew Chem Int Ed Engl, 52:12187-12191
(2013)

Tags: Medicinal Chemistry (Rademann), Screening Unit (von Kries), Solution NMR (Schmieder)

Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
Posor, Y., Eichhorn-Grünig, M., Puchkov, D., Schöneberg(*), J., Ullrich(*), A., Lampe, A., Müller(*), R., Zarbakhsh(*), S., Gulluni(*), F., Hirsch(*), E., Krauss, M., Schultz(*), C., Schmoranzer, J., Noe(*), F.; Haucke, V.
Nature, 499:233-+
(2013)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic(1,2). Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits(3-6). No phosphatidylinositol other than PI(4,5)P-2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P)(7). How phosphatidylinositol conversion from PI(4,5)P-2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P-2) by class II phosphatidylinositol-3-kinase C2 alpha (PI(3) K C2 alpha) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P-2 or PI(3)K C2 alpha impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P-2 by PI(3)K C2 alpha is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P-2 in endocytosis and unravel a novel discrete function of PI(3,4)P-2 in a central cell physiological process.

PI4K2beta/AP-1-based TGN-endosomal sorting regulates Wnt signaling
Wieffer, M., Cibrian Uhalte(*), E., Posor, Y., Otten(*), C., Branz, K., Schütz, I., Mössinger, J., Schu(*), P., Abdelilah-Seyfried(*), S., Krauss, M.; Haucke, V.
Curr Biol, 23:2185-2190
(2013)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Endosomal membrane traffic serves crucial roles in cell physiology, signaling, and development. Sorting between endosomes and the trans-Golgi network (TGN) is regulated among other factors by the adaptor AP-1, an essential component of multicellular organisms. Membrane recruitment of AP-1 requires phosphatidylinositol 4-phosphate [PI(4)P], though the precise mechanisms and PI4 kinase isozyme (or isozymes) involved in generation of this PI(4)P pool remain unclear. The Wnt pathway is a major developmental signaling cascade and depends on endosomal sorting in Wnt-sending cells. Whether TGN/endosomal sorting modulates signaling downstream of Frizzled (Fz) receptors in Wnt-receiving cells is unknown. Here, we identify PI4-kinase type 2beta (PI4K2beta) as a regulator of TGN/endosomal sorting and Wnt signaling. PI4K2beta and AP-1 interact directly and are required for efficient sorting between endosomes and the TGN. Zebrafish embryos depleted of PI4K2beta or AP-1 lack pectoral fins due to defective Wnt signaling. Rescue experiments demonstrate requirements for PI4K2beta-AP-1 complex formation and PI4K2beta-mediated PI(4)P synthesis. Furthermore, PI4K2beta binds to the Fz-associated component Dishevelled (Dvl) and regulates endosomal recycling of Fz receptors and Wnt target gene expression. These data reveal an evolutionarily conserved role for PI4K2beta and AP-1 in coupling phosphoinositide metabolism to AP-1-mediated sorting and Wnt signaling.

The Bacterial Translocon SecYEG Opens upon Ribosome Binding
Knyazev(*), D. G., Lents(*), A., Krause, E., Ollinger(*), N., Siligan(*), C., Papinski(*), D., Winter(*), L., Horner(*), A.; Pohl(*), P.
Journal of Biological Chemistry, 288:17941-17946
(2013)

Tags: Mass Spectrometry (Krause, E.)

Abstract: In co-translational translocation, the ribosome funnel and the channel of the protein translocation complex SecYEG are aligned. For the nascent chain to enter the channel immediately after synthesis, a yet unidentified signal triggers displacement of the SecYEG sealing plug from the pore. Here, we show that ribosome binding to the resting SecYEG channel triggers this conformational transition. The purified and reconstituted SecYEG channel opens to form a large ion-conducting channel, which has the conductivity of the plug deletion mutant. The number of ion-conducting channels inserted into the planar bilayer per fusion event roughly equals the number of SecYEG channels counted by fluorescence correlation spectroscopy in a single proteoliposome. Thus, the open probability of the channel must be close to unity. To prevent the otherwise lethal proton leak, a closed post-translational conformation of the SecYEG complex bound to a ribosome must exist.

CRIS-A Novel cAMP-Binding Protein Controlling Spermiogenesis and the Development of Flagellar Bending
Krähling(*), A. M., Alvarez(*), L., Debowski(*), K., Van(*), Q., Gunkel(*), M., Irsen(*), S., Al-Amoudi(*), A., Strünker(*), T., Kremmer(*), E., Krause, E., Voigt(*), I., Wortge(*), S., Waisman(*), A., Weyand(*), I., Seifert(*), R., Kaupp(*), U. B.; Wachten(*), D.
Plos Genet, 9
(2013)

Tags: Mass Spectrometry (Krause, E.)

Abstract: The second messengers cAMP and cGMP activate their target proteins by binding to a conserved cyclic nucleotide-binding domain (CNBD). Here, we identify and characterize an entirely novel CNBD-containing protein called CRIS (cyclic nucleotide receptor involved in sperm function) that is unrelated to any of the other members of this protein family. CRIS is exclusively expressed in sperm precursor cells. Cris-deficient male mice are either infertile due to a lack of sperm resulting from spermatogenic arrest, or subfertile due to impaired sperm motility. The motility defect is caused by altered Ca2+ regulation of flagellar beat asymmetry, leading to a beating pattern that is reminiscent of sperm hyperactivation. Our results suggest that CRIS interacts during spermiogenesis with Ca2+-regulated proteins that-in mature sperm-are involved in flagellar bending.

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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
+4930 94793 - 100 
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info(at)fmp-berlin.de

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