FMP Publications

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

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References
Differences in Signal Activation by LH and hCG are Mediated by the LH/CG Receptor's Extracellular Hinge Region
Grzesik, P., Kreuchwig, A., Rutz, C., Furkert, J., Wiesner, B., Schülein, R., Kleinau(*), G., Gromoll(*), J.; Krause, G.
Front Endocrinol (Lausanne), 6:140
(2015)

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

Abstract: The human lutropin (hLH)/choriogonadotropin (hCG) receptor (LHCGR) can be activated by binding two slightly different gonadotropic glycoprotein hormones, choriogonadotropin (CG) - secreted by the placenta, and lutropin (LH) - produced by the pituitary. They induce different signaling profiles at the LHCGR. This cannot be explained by binding to the receptor's leucine-rich-repeat domain (LRRD), as this binding is similar for the two hormones. We therefore speculate that there are previously unknown differences in the hormone/receptor interaction at the extracellular hinge region, which might help to understand functional differences between the two hormones. We have therefore performed a detailed study of the binding and action of LH and CG at the LHCGR hinge region. We focused on a primate-specific additional exon in the hinge region, which is located between LRRD and the serpentine domain. The segment of the hinge region encoded by exon10 was previously reported to be only relevant to hLH signaling, as the exon10-deletion receptor exhibits decreased hLH signaling, but unchanged hCG signaling. We designed an advanced homology model of the hormone/LHCGR complex, followed by experimental characterization of relevant fragments in the hinge region. In addition, we examined predictions of a helical exon10-encoded conformation by block-wise polyalanine (helix supporting) mutations. These helix preserving modifications showed no effect on hormone-induced signaling. However, introduction of a structure-disturbing double-proline mutant LHCGR-Q303P/E305P within the exon10-helix has, in contrast to exon10-deletion, no impact on hLH, but only on hCG signaling. This opposite effect on signaling by hLH and hCG can be explained by distinct sites of hormone interaction in the hinge region. In conclusion, our analysis provides details of the differences between hLH- and hCG-induced signaling that are mainly determined in the L2-beta loop of the hormones and in the hinge region of the receptor.

Depletion of highly abundant proteins from human cerebrospinal fluid: a cautionary note
Günther, R., Krause, E., Schümann, M., Blasig, I. E.; Haseloff, R. F.
Mol Neurodegener, 10:53
(2015)

Tags: Molecular Cell Physiology (Blasig, I.E.), Mass Spectrometry (Krause, E.)

Abstract: Affinity-based techniques, both for enrichment or depletion of proteins of interest, suffer from unwanted interactions between the bait or matrix material and molecules different from the original target. This effect was quantitatively studied by applying two common procedures for the depletion of albumin/gamma immunoglobulin to human cerebrospinal fluid. Proteins of the depleted and the column-bound fraction were identified by mass spectrometry, employing (18)O labeling for quantitation of their abundance. To different extents, the depletion procedures caused the loss of proteins previously suggested as biomarker candidates for neurological diseases. This is an important phenomenon to consider when quantifying protein levels in biological fluids.

Hybrid Structure of the Type 1 Pilus of Uropathogenic Escherichia coli
Habenstein(*), B., Loquet(*), A., Hwang, S., Giller(*), K., Vasa(*), S. K., Becker(*), S., Habeck(*), M.; Lange, A.
Angew Chem Int Ed Engl, 54:11691-11695
(2015)

Tags: Molecular Biophysics (Lange, A.)

Abstract: Type 1 pili are filamentous protein assemblies on the surface of Gram-negative bacteria that mediate adhesion to host cells during the infection process. The molecular structure of type 1 pili remains elusive on the atomic scale owing to their insolubility and noncrystallinity. Herein we describe an approach for hybrid-structure determination that is based on data from solution-state NMR spectroscopy on the soluble subunit and solid-state NMR spectroscopy and STEM data on the assembled pilus. Our approach is based on iterative modeling driven by structural information extracted from different sources and provides a general tool to access pseudo atomic structures of protein assemblies with complex subunit folds. By using this methodology, we determined the local conformation of the FimA pilus subunit in the context of the assembled type 1 pilus, determined the exact helical pilus architecture, and elucidated the intermolecular interfaces contributing to pilus assembly and stability with atomic detail.

Editorial overview: Synthetic biomolecules: Synthetic protein modifications-a giant leap towards understanding and generating biological functions
Hackenberger, C. P.; Chen(*), P. R.
Curr Opin Chem Biol, 28:vii-ix
(2015)

Tags: Chemical Biology II (Hackenberger)

Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors
Halland(*), N., Schmidt(*), F., Weiss(*), T., Saas(*), J., Li(*), Z., Czech(*), J., Dreyer(*), M., Hofmeister(*), A., Mertsch(*), K., Dietz(*), U., Strübing(*), C.; Nazare, M.
Acs Med Chem Lett, 6:73-78
(2015)

Tags: Medicinal Chemistry (Nazare)

Abstract: From a virtual screening starting point, inhibitors of the serum and glucocorticoid regulated kinase 1 were developed through a combination of classical medicinal chemistry and library approaches. This resulted in highly active small molecules with nanomolar activity and a good overall in vitro and ADME profile. Furthermore, the compounds exhibited unusually high kinase and off-target selectivity due to their rigid structure.

Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects
Haseloff, R. F., Dithmer, S., Winkler, L., Wolburg, H.; Blasig, I. E.
Semin Cell Dev Biol, 38:16-25
(2015)

Tags: Molecular Cell Physiology (Blasig, I.E.)

Abstract: The blood-brain barrier (BBB) is formed by microvascular endothelial cells sealed by tetraspanning tight junction (TJ) proteins, such as claudins and TAMPs (TJ-associated marvel proteins, occludin and tricellulin). Claudins are the major components of the TJs. At the BBB, claudin-5 dominates the TJs by preventing the paracellular permeation of small molecules. On the other hand, TAMPs regulate the structure and function of the TJs; tricellulin may tighten the barrier for large molecules. This review aims at integrating and summarizing the most relevant and recent work on how the BBB is influenced by claudin-1, -3, -5, -12 and the TAMPs occludin and tricellulin, all of which are four-transmembrane TJ proteins. The exact functions of claudin-1, -3, -12 and TAMPs at this barrier still need to be elucidated.

Cell biology: On the endocytosis rollercoaster
Haucke, V.
Nature, 517:446-447
(2015)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Hopping Pits Catch Fusing Granules
Haucke, V.
Dev Cell, 35:10-11
(2015)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: In excitable cells, regulated exocytosis is coupled to endocytic membrane retrieval. Yuan et al. (2015) in this issue of Developmental Cell report a possible mechanism for such exo-endocytic coupling that is based on stimulation-induced hopping of clathrin-containing endocytic structures to nascent sites of insulin granule fusion.

Gottfried Schatz (1936-2015)-mitochondrial pioneer and ambassador for science
Haucke, V.; Glick(*), B. S.
EMBO J, 34:2725-2726
(2015)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Plasma proteomic analysis of active and torpid greater mouse-eared bats (Myotis myotis)
Hecht(*), A. M., Braun(*), B. C., Krause, E., Voigt(*), C. C., Greenwood(*), A. D.; Czirjak(*), G. A.
Sci Rep, 5:16604
(2015)

Tags: Mass Spectrometry (Krause, E.)

Abstract: Hibernation is a physiological adaptation to overcome extreme environmental conditions. It is characterized by prolonged periods of torpor interrupted by temporary arousals during winter. During torpor, body functions are suppressed and restored rapidly to almost pre-hibernation levels during arousal. Although molecular studies have been performed on hibernating rodents and bears, it is unclear how generalizable the results are among hibernating species with different physiology such as bats. As targeted blood proteomic analysis are lacking in small hibernators, we investigated the general plasma proteomic profile of European Myotis myotis and hibernation associated changes between torpid and active individuals by two-dimensional gel electrophoresis. Results revealed an alternation of proteins involved in transport, fuel switching, innate immunity and blood coagulation between the two physiological states. The results suggest that metabolic changes during hibernation are associated with plasma proteomic changes. Further characterization of the proteomic plasma profile identified transport proteins, coagulation proteins and complement factors and detected a high abundance of alpha-fetoprotein. We were able to establish for the first time a basic myotid bat plasma proteomic profile and further demonstrated a modulated protein expression during torpor in Myotis myotis, indicating both novel physiological pathways in bats in general, and during hibernation in particular.

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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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