FMP Publications

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

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TRIM24 links a non-canonical histone signature to breast cancer
Tsai(*), W. W., Wang(*), Z. X., Yiu(*), T. T., Akdemir(*), K. C., Xia(*), W. Y., Winter(*), S., Tsai(*), C. Y., Shi(*), X. B., Schwarzer, D., Plunkett(*), W., Aronow(*), B., Gozani(*), O., Fischle(*), W., Hung(*), M. C., Patel(*), D. J.; Barton(*), M. C.
Nature, 468:927-U320

Tags: Protein Chemistry (Schwarzer)

Abstract: Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.

Chemical tools in chromatin research
Schwarzer, D.
J Pept Sci, 16:530-537

Tags: Protein Chemistry (Schwarzer)

Abstract: Eukaryotes organize their DNA in the form of chromatin. This complex of DNA and packaging proteins, the histones, ensures that all genomic information fits into the limited space of the cell nucleus. In addition to compacting DNA, chromatin itself regulates the activity of encoded genes. This regulatory process involves many posttranslational modifications of histone proteins and deciphering the complex crosstalk between histone modifications and gene activity represents a central challenge for biomedical science. This task has often been supported by sophisticated chemical tools, which were crucial for many important discoveries in this field. This review provides an overview of chemical tools for chromatin research, with emphasis on classical and current examples of their applications.

Simultaneous detection of protein phosphorylation and acetylation by high-resolution NMR spectroscopy
Liokatis, S., Dose, A., Schwarzer, D.; Selenko, P.
J Am Chem Soc, 132:14704-14705

Tags: In-Cell NMR (Selenko), Protein Chemistry (Schwarzer)

Abstract: Post-translational protein modifications (PTMs) such as phosphorylation and acetylation regulate a large number of eukaryotic signaling processes. In most instances, it is the combination of different PTMs that "encode" the biological outcome of these covalent amendments in a highly dynamic and cell-state-specific manner. Most research tools fail to detect different PTMs in a single experiment and are unable to directly observe dynamic PTM states in complex environments such as cell extracts or intact cells. Here we describe in situ observations of phosphorylation and acetylation reactions by high-resolution liquid-state NMR spectroscopy. We delineate the NMR characteristics of progressive lysine acetylation and provide in vitro examples of joint phosphorylation and acetylation events and how they can be deciphered on a residue-specific basis and in a time-resolved and quantitative manner. Finally, we extend our NMR investigations to cellular phosphorylation and acetylation events in human cell extracts and demonstrate the unique ability of NMR spectroscopy to simultaneously report the establishment of these PTMs by endogenous cellular enzymes.

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)

Design, synthesis, structure and binding properties of PDZ binding, cyclic beta-finger peptides
Seedorff, S., Appelt, C., Beyermann, M.; Schmieder, P.
Biochem Biophys Res Commun, 395:535-539

Tags: Solution NMR (Schmieder), Peptide Synthesis (Beyermann)

Abstract: Protein interaction domains (PIDs) play a critical role in signal transduction. One PID of great interest is the PDZ domain, a 100 amino-acid-residue domain. Most PDZ domains recognize short, C-terminal peptide motives. In the heterodimer of the nNOS-PDZ domain and the alpha-syntrophin-PDZ domain, however, one PDZ domain forms a beta-finger that binds to the other PDZ domain. We show here that cyclic peptides derived from the beta-finger of the nNOS-PDZ domain can bind the syntrophin-PDZ domain in the same manner as the whole domain. The structure of three "finger-peptides" of different size has been determined and the binding investigated using calorimetry and NMR-titration experiments.

NMR spectroscopic investigation of mobility and hydrogen bonding of the chromophore in the binding pocket of phytochrome proteins
Röben, M., Hahn, J., Klein, E., Lamparter(*), T., Psakis(*), G., Hughes(*), J.; Schmieder, P.
Chemphyschem, 11:1248-1257

Tags: Solution NMR (Schmieder)

Abstract: For a complete understanding of the light reception of phytochrome proteins, a detailed study of the structure and dynamics of the binding pocket at atomic resolution is required. Structures from X-ray crystallography and NMR spectroscopy are available and have been able to provide a picture of the binding pocket. NMR spectroscopy has, in addition, shown that the chromophore exhibits noticeable dynamics in the binding pocket of the cyanobacterial phytochrome Cph1. Herein, NMR spectroscopy is used to investigate further the mobility of the chromophore by analyzing the line widths of the resonances of the chromophore in various environments, in particular other protein environments. It is shown that the chromophore exhibits a different mobility in the binding pocket of the bacterial phytochrome Agp1 than in that of the cyanobacterial phytochrome Cph1. Finally, it is shown that NMR spectroscopy is capable of detecting hydrogen bonds in the binding pocket of phytochromes by observing slow exchange of protons in the amino acid side chains.

High Resolution H-1-Detected Solid-State NMR Spectroscopy of Protein Aliphatic Resonances: Access to Tertiary Structure Information
Asami, S., Schmieder, P.; Reif, B.
J. Am. Chem. Soc., 132:15133-15135

Tags: Solid-State NMR Spectroscopy (Reif), Solution NMR (Schmieder)

Abstract: Biological magic angle spinning (MAS) solid-state nuclear magnetic resonance spectroscopy has developed rapidly over the past two decades. For the structure determination of a protein by solid-state NMR, routinely C-13,C-13 distance restraints as well as dihedral restraints are employed. In protonated samples, this is achieved by growing the bacterium on a medium which contains [1,3]-C-13 glycerol or [2]-C-13 glycerol to dilute the C-13 spin system. Labeling schemes, which rely on heteronuclei, are insensitive both for detection and in terms of quantification of distances, since they are relying on low-gamma nuclei. Proton detection can in principle provide a gain in sensitivity by a factor of 8 and 31, compared to the C-13 or N-15 detected version of the experiment. We report here a new labeling scheme, which enables H-1-detection of aliphatic resonances with high resolution in MAS solid-state NMR spectroscopy. We prepared microcrystals of the SH3 domain of chicken a-spectrin with 5% protonation at nonexchangeable sites and obtained line widths on the order of 25 Hz for aliphatic H-1 resonances. We show further that C-13 resolved 3D-H-1,H-1 correlation experiments yield access to long-range proton-proton distances in the protein.

Amino-terminal fragment of C-type natriuretic peptide precursor and C-type natriuretic peptide do not correlate in patients with Chagas disease: role for neutral endopeptidase
Wang(*), Y., Moreira Mda(*), C., Heringer-Walther(*), S., Schultheiss(*), H. P., Siems, W. E., Wessel(*), N.; Walther(*), T.
Journal of cardiovascular pharmacology, 55:62-66

Tags: Biochemical Neurobiology (Siems)

Abstract: Atrial and B-type natriuretic peptides (ANP and BNP), but not C-type natriuretic peptide (CNP), have been identified to be diagnostic and prognostic markers in Chagas disease (CD). Although ANP and BNP excessively rise in patients with CD, increase in CNP is just minor. Our study aimed to investigate the mechanisms leading to CNP insensitivity to heart failure (HF) stimuli. Amino-terminal fragment of CNP precursor (NT-proCNP) and activity of neutral endopeptidase (NEP) were quantified to monitor CNP generation and degradation, respectively. Blood samples were collected from patients with CD and control healthy subjects. NT-proCNP concentrations were significantly lower in patients with CD without systolic dysfunction compared with healthy subjects. Despite a trend toward increase with rising heart failure clinical severity, it was significantly correlated with left ventricular ejection fraction and other echocardiographic parameters. As shown for CNP before, NT-proCNP could not predict mortality and heart transplant. Importantly, it had no statistical correlation with CNP. Additionally, NEP activity was significantly increased in New York Heart Association III and IV patients with HF but was positively correlated with CNP concentration. Our data demonstrates that generation of CNP is not enhanced under HF condition like CD. Thus, CNP rise by severe HF is caused by its less degradation that is independent of NEP activity.

Plasma ACE2 activity is an independent prognostic marker in Chagas' disease and equally potent as BNP
Wang(*), Y., Moreira Mda(*), C., Heringer-Walther(*), S., Ebermann(*), L., Schultheiss(*), H. P., Wessel(*), N., Siems, W. E.; Walther(*), T.
Journal of cardiac failure, 16:157-163

Tags: Biochemical Neurobiology (Siems)

Abstract: BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is a novel homologue of ACE. It metabolizes angiotensin (Ang)II to Ang-(1-7). This study aims to investigate the diagnostic and prognostic potency of circulating ACE2 activity in patients with heart failure (HF) from Chagas' disease (CD). METHODS AND RESULTS: Blood samples were obtained from 111 CD patients and 40 age- and gender-matched healthy subjects. The CD patients were further subdivided according to their New York Heart Association classification. ACE2 activity was significantly increased in CD patients with HF, but not in patients without systolic dysfunction. Moreover, plasma ACE2 activity was significantly correlated with their clinical severity and echocardiographic parameters. Importantly, the potency of circulating ACE2 activity in CD patients was equally potent as that of B-type natriuretic peptide to predict cardiac death and heart transplant. Most importantly, patients with both parameters elevated were on a 5-fold higher risk to reach an endpoint than patients with increase in only 1 of the 2 parameters. CONCLUSIONS: Determination of ACE2 activity may provide a new and important diagnostic and prognostic marker for patients with CD. ACE2 activity and BNP concentration have additive predictive value and may be used in combination to offer a new dimension of prediction in HF.

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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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