FMP Publications

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

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Tool for the Chemical Biology
Hackenberger(*), C. P. R., Arndt(*), H. D.; Schwarzer, D.
Chem Unserer Zeit, 44:198-206

Tags: Protein Chemistry (Schwarzer)

Arndt(*), H. D., Hackenberger(*), C. P. R.; Schwarzer, D.
Chem Unserer Zeit, 44:130-137

Tags: Protein Chemistry (Schwarzer)

Bidirectional binding of invariant chain peptides to an MHC class II molecule
Günther, S., Schlundt, A., Sticht, J., Roske(*), Y., Heinemann(*), U., Wiesmüller(*), K. H., Jung(*), G., Falk(*), K., Rötzschke(*), O.; Freund, C.
Proc Natl Acad Sci U S A, 107:22219-22224

Tags: Protein Engineering (Freund)

Abstract: T-cell recognition of peptides bound to MHC class II (MHCII) molecules is a central event in cell-mediated adaptive immunity. The current paradigm holds that prebound class II-associated invariant chain peptides (CLIP) and all subsequent antigens maintain a canonical orientation in the MHCII binding groove. Here we provide evidence for MHCII-bound CLIP inversion. NMR spectroscopy demonstrates that the interconversion from the canonical to the inverse alignment is a dynamic process, and X-ray crystallography shows that conserved MHC residues form a hydrogen bond network with the peptide backbone in both orientations. The natural catalyst HLA-DM accelerates peptide reorientation and the exchange of either canonically or inversely bound CLIP against antigenic peptide. Thus, noncanonical MHC-CLIP displays the hallmarks of a structurally and functionally intact antigen-presenting complex.

[8-[Bis(carboxymethyl)aminomethyl]-6-bromo-7-hydroxycoumarin-4-yl]methyl moieties as photoremovable protecting groups for compounds with COOH, NH2, OH, and C=O functions
Hagen, V., Kilic, F., Schaal, J., Dekowski, B., Schmidt(*), R.; Kotzur, N.
J Org Chem, 75:2790-2797

Tags: Synthetic Organic Biochemistry (Hagen)

Abstract: We introduce a variant of coumarin-based photoactivatable protecting groups and use it exemplarily for caging of a carboxylic acid, an amine, a phenol, and a carbonyl compound. The caged compounds are efficiently photolyzed at long-wavelength UV/vis irradiation. Compared to the corresponding (6-bromo-7-hydroxycoumarin-4-yl)methyl (Bhc) derivatives, the novel coumarin-type caged compounds are distinguished by (i) dramatically increased solubilities in aqueous buffers, (ii) lower pK(a) values of the C7 hydroxyl of the coumarin chromophore, thus permitting efficient photorelease at lower pH, and (iii) higher photolysis quantum yields in the case of photoprotected carbonyl compounds. The primary step of the photocleavages occurs with rate constants of about 10(9) s(-1).

The Investigation of cis- and trans-Interactions Between Claudins
Haseloff, R. F., Piontek, J.; Blasig, I. E.
Curr Top Membr, 65:97-112

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

Abstract: OVERVIEW Claudins control the paracellular permeability of the tight junctions in epithelial and endothelial cells forming single cell layers. Several claudins may constitute a network of strands, establishing a continuous barrier within the intercellular clefts of the monolayer. Depending on the claudin composition of a given tissue, the intracellular space may be tight for any solute or permeable for compounds of different molecular weight or differently charged ions. These functions are largely based on intermolecular claudin claudin interactions. Strand formation between claudins requires two components: a longitudinal association along the plasma membrane of the cell-cis-interaction-and an interplay from one cell surface to the next one-trans-interaction. This chapter is aimed at reviewing methods for the analysis of cis- and trans-interacting claudins.

Short Cationic Antimicrobial Peptides Interact with ATP
Hilpert(*), K., McLeod(*), B., Yu(*), J., Elliott(*), M. R., Rautenbach(*), M., Ruden(*), S., Bürck(*), J., Muhle-Goll(*), C., Ulrich(*), A. S., Keller, S.; Hancock(*), R. E. W.
Antimicrob Agents Ch, 54:4480-4483

Tags: Biophysics of Membrane Proteins (Keller)

Abstract: The mode of action of short, nonhelical antimicrobial peptides is still not well understood. Here we show that these peptides interact with ATP and directly inhibit the actions of certain ATP-dependent enzymes, such as firefly luciferase, DnaK, and DNA polymerase. alpha-Helical and planar or circular antimicrobial peptides did not show such interaction with ATP.

Glycogen synthase kinase 3beta interaction protein functions as an A-kinase anchoring protein
Hundsrucker, C., Skroblin, P., Christian, F., Zenn(*), H. M., Popara, V., Joshi, M., Eichhorst, J., Wiesner, B., Herberg(*), F. W., Reif, B., Rosenthal(*), W.; Klussmann, E.
J Biol Chem, 285:5507-5521

Tags: Anchored Signalling (Klussmann), Solid-State NMR Spectroscopy (Reif), Cellular Imaging (Wiesner)

Abstract: A-kinase anchoring proteins (AKAPs) include a family of scaffolding proteins that target protein kinase A (PKA) and other signaling proteins to cellular compartments and thereby confine the activities of the associated proteins to distinct regions within cells. AKAPs bind PKA directly. The interaction is mediated by the dimerization and docking domain of regulatory subunits of PKA and the PKA-binding domain of AKAPs. Analysis of the interactions between the dimerization and docking domain and various PKA-binding domains yielded a generalized motif allowing the identification of AKAPs. Our bioinformatics and peptide array screening approaches based on this signature motif identified GSKIP (glycogen synthase kinase 3beta interaction protein) as an AKAP. GSKIP directly interacts with PKA and GSK3beta (glycogen synthase kinase 3beta). It is widely expressed and facilitates phosphorylation and thus inactivation of GSK3beta by PKA. GSKIP contains the evolutionarily conserved domain of unknown function 727. We show here that this domain of GSKIP and its vertebrate orthologues binds both PKA and GSK3beta and thereby provides a mechanism for the integration of PKA and GSK3beta signaling pathways.

A novel subtype of AP-1-binding motif within the palmitoylated trans-Golgi network/endosomal accessory protein Gadkin/gamma-BAR
Maritzen(*), T., Schmidt(*), M. R., Kukhtina(*), V., Higman, V. A., Strauss, H., Volkmer(*), R., Oschkinat, H., Dotti(*), C. G.; Haucke, V.
J Biol Chem, 285:4074-4086

Tags: Molecular Pharmacology and Cell Biology (Haucke), Protein Structure (Oschkinat)

Abstract: Membrane traffic between the trans-Golgi network (TGN) and endosomes is mediated in part by the assembly of clathrin-AP-1 adaptor complex-coated vesicles. This process involves multiple accessory proteins that directly bind to the ear domain of AP-1gamma via degenerate peptide motifs that conform to the consensus sequence diameterG(P/D/E)(diameter/L/M) (with diameter being a large hydrophobic amino acid). Recently, gamma-BAR (hereafter referred to as Gadkin for reasons explained below) has been identified as a novel AP-1 recruitment factor involved in AP-1-dependent endosomal trafficking of lysosomal enzymes. How precisely Gadkin interacts with membranes and with AP-1gamma has remained unclear. Here we show that Gadkin is an S-palmitoylated peripheral membrane protein that lacks stable tertiary structure. S-Palmitoylation is required for the recruitment of Gadkin to TGN/endosomal membranes but not for binding to AP-1. Furthermore, we identify a novel subtype of AP-1-binding motif within Gadkin that specifically associates with the gamma1-adaptin ear domain. Mutational inactivation of this novel type of motif, either alone or in combination with three more conventional AP-1gamma binding peptides, causes Gadkin to mislocalize to the plasma membrane and interferes with its ability to render AP-1 brefeldin A-resistant, indicating its physiological importance. Our studies thus unravel the molecular basis for Gadkin-mediated AP-1 recruitment to TGN/endosomal membranes and identify a novel subtype of the AP-1-binding motif.

Solid-state NMR and SAXS studies provide a structural basis for the activation of alphaB-crystallin oligomers
Jehle, S., Rajagopal(*), P., Bardiaux, B., Markovic, S., Kühne, R., Stout(*), J. R., Higman, V. A., Klevit(*), R. E., van Rossum, B. J.; Oschkinat, H.
Nat Struct Mol Biol, 17:1037-1042

Tags: Protein Structure (Oschkinat), Computational Chemistry/ Drug Design (Kühne)

Abstract: The small heat shock protein alphaB-crystallin (alphaB) contributes to cellular protection against stress. For decades, high-resolution structural studies on oligomeric alphaB have been confounded by its polydisperse nature. Here, we present a structural basis of oligomer assembly and activation of the chaperone using solid-state NMR and small-angle X-ray scattering (SAXS). The basic building block is a curved dimer, with an angle of approximately 121 degrees between the planes of the beta-sandwich formed by alpha-crystallin domains. The highly conserved IXI motif covers a substrate binding site at pH 7.5. We observe a pH-dependent modulation of the interaction of the IXI motif with beta4 and beta8, consistent with a pH-dependent regulation of the chaperone function. N-terminal region residues Ser59-Trp60-Phe61 are involved in intermolecular interaction with beta3. Intermolecular restraints from NMR and volumetric restraints from SAXS were combined to calculate a model of a 24-subunit alphaB oligomer with tetrahedral symmetry.

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27
Kamilic(*), J., Hamming(*), I., Kreutz(*), R., Bolbrinker(*), J., Siems, W. E., Nassar(*), I., Sluimer(*), J. C., Walther(*), T., Navis(*), G. J.; van Goor(*), H.
Hypertens Res, 33:123-128

Tags: Biochemical Neurobiology (Siems)

Abstract: Differential renal expression of a homolog of the angiotensin-converting enzyme (ACE), that is, ACE2, has been implicated as a genetic basis of polygenetic hypertension in the stroke-prone spontaneously hypertensive rat model. However, data on the role of ACE2 in hypertension are still inconclusive. Therefore, we analyzed kidney ACE2 mRNA, ACE2 protein and ACE2 enzyme activities in the adult polygenetic stroke-prone spontaneously hypertensive rat (SHRSP) and the monogenetic TGR(mREN2)27 rat models, in comparison with their normotensive reference strains, Wistar-Kyoto (WKY) and Spraque-Dawley (SD) rats, respectively. Kidney ACE2 mRNA was studied using quantitative real-time reverse transcriptase-PCR (RT-PCR) in cortex and medulla, whereas protein expression was scored semiquantitatively in detail in different renal structures using immunohistochemistry. Furthermore, total renal tissue ACE2 activity was measured using a fluorimetric assay that was specified by the ACE2 inhibitor DX600. In SHRSP and homozygous TGR(mREN2)27 rats with established hypertension, kidney ACE2 mRNA, protein and tissue ACE2 activities were not different from their respective WKY and SD reference strain, respectively. In addition, when we looked at renal localization, we found ACE2 protein to be predominantly present in glomeruli and endothelium with weak staining in distal and negative staining in proximal tubuli. Thus, our data challenge previous work that implicates ACE2 as a candidate gene for hypertension in SHRSP by reporting a significant reduction of ACE2 in the kidneys of SHRSP. Taken together, renal ACE2 is not altered in the SHRSP and TGR(mREN2)27 genetic rat models with established hypertension. Hypertension Research (2010) 33, 123-128; doi: 10.1038/hr.2009.191; published online 20 November 2009

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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)

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