FMP Publications

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

All :: 2010, 2014, 2015, 2016, 2017
All :: (, A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z 
All :: Xi(*), ... , Xiang(*), Xiao(*), Xiong(*), ... , Xue(*) 
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A Two-Component Adhesive: Tau Fibrils Arise from a Combination of a Well-Defined Motif and Conformationally Flexible Interactions
Xiang(*), S. Q., Kulminskaya(*), N., Habenstein(*), B., Biernat(*), J., Tepper(*), K., Paulat(*), M., Griesinger(*), C., Becker(*), S., Lange, A., Mandelkow(*), E.; Linser(*), R.
J. Am. Chem. Soc., 139:2639-2646

Tags: Molecular Biophysics (Lange, A.)

Abstract: Fibrillar aggregates of A beta and Tau in the brain are the major hallmarks of Alzheimer's disease. Most Tau fibers have a twisted appearance, but the twist can be variable and even absent. This ambiguity, which has also been associated with different phenotypes of tauopathies, has led to controversial assumptions about fibril constitution, and it is unclear to-date what the molecular causes of this polymorphism are. To tackle this question, we used solid-state NMR strategies providing assignments of non-seeded three-repeat-domain Tau(3RD) with an inherent heterogeneity. This is in contrast to the general approach to characterize the most homogeneous preparations by construct truncation or intricate seeding protocols. Here, carbon and nitrogen chemical-shift conservation between fibrils revealed invariable secondary-structure properties, however, with inter-monomer interactions variable among samples. Residues with variable amide shifts are localized mostly to N- and C-terminal regions within the rigid beta structure in the repeat region of Tau(3RD). By contrast, the hexapeptide motif in repeat R3, a crucial motif for fibril formation, shows strikingly low variability of all NMR parameters: Starting as a nucleation site for monomer monomer contacts, this six-residue sequence element also turns into a well-defined structural element upon fibril formation. Given the absence of external causes in vitro, the interplay of structurally differently conserved elements in this protein likely reflects an intrinsic property of Tau fibrils.

A Self-Assembled Oligopeptide as a Versatile NMR Alignment Medium for the Measurement of Residual Dipolar Couplings in Methanol
Lei(*), X. X., Qiu(*), F., Sun, H., Bai(*), L. W., Wang(*), W. X., Xiang(*), W. S.; Xiao(*), H. P.
Angew Chem Int Edit, 56:12857-12861

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Residual dipolar coupling (RDC) is a powerful structural parameter for the determination of the constitution, conformation, and configuration of organic molecules. Herein, we report the first liquid crystal-based orienting medium that is compatible with MeOH, thus enabling RDC acquisitions of a wide range of intermediate to polar organic molecules. The liquid crystals were produced from self-assembled oligopeptide nanotubes (AAKLVFF), which are stable at very low concentrations. The presented alignment medium is highly homogeneous, and the size of RDCs can be scaled with the concentration of the peptide. To assess the accuracy of the RDC measurement by employing this new medium, seven bioactive natural products from different classes were chosen and analyzed. The straightforward preparation of the anisotropic alignment sample will offer a versatile and robust protocol for the routine RDC measurement of natural products.


Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
Stempel(*), A. V., Stumpf(*), A., Zhang(*), H. Y., Ozdogan(*), T., Pannasch(*), U., Theis(*), A. K., Otte(*), D. M., Wojtalla(*), A., Racz(*), I., Ponomarenko, A., Xi(*), Z. X., Zimmer(*), A.; Schmitz(*), D.
Neuron, 90:795-809

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.


Perspectives for sensitivity enhancement in proton-detected solid-state NMR of highly deuterated proteins by preserving water magnetization
Chevelkov, V., Xiang(*), S. Q., Giller(*), K., Becker(*), S., Lange, A.; Reif(*), B.
J. Biomol. NMR, 61:151-160

Tags: Molecular Biophysics (Lange, A.)

Abstract: In this work, we show how the water flip-back approach that is widely employed in solution-state NMR can be adapted to proton-detected MAS solid-state NMR of highly deuterated proteins. The scheme allows to enhance the sensitivity of the experiment by decreasing the recovery time of the proton longitudinal magnetization. The method relies on polarization transfer from non-saturated water to the protein during the inter-scan delay.

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs
Planells-Cases, R., Lutter, D., Guyader(*), C., Gerhards(*), N. M., Ullrich, F., Elger, D. A., Kucukosmanoglu(*), A., Xu(*), G., Voss, F. K., Reincke, S. M., Stauber, T., Blomen(*), V. A., Vis(*), D. J., Wessels(*), L. F., Brummelkamp(*), T. R., Borst(*), P., Rottenberg(*), S.; Jentsch, T. J.
EMBO J, 34:2993-3008

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.


Site-specific analysis of heteronuclear Overhauser effects in microcrystalline proteins
del Amo, J. M. L., Agarwal, V., Sarkar(*), R., Porter(*), J., Asami(*), S., Rubbelke(*), M., Fink, U., Xue(*), Y., Lange(*), O. F.; Reif, B.
J. Biomol. NMR, 59:241-249

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Relaxation parameters such as longitudinal relaxation are susceptible to artifacts such as spin diffusion, and can be affected by paramagnetic impurities as e.g. oxygen, which make a quantitative interpretation difficult. We present here the site-specific measurement of [H-1]C-13 and [H-1]N-15 heteronuclear rates in an immobilized protein. For methyls, a strong effect is expected due to the three-fold rotation of the methyl group. Quantification of the [H-1]C-13 heteronuclear NOE in combination with C-13-R (1) can yield a more accurate analysis of side chain motional parameters. The observation of significant [H-1]N-15 heteronuclear NOEs for certain backbone amides, as well as for specific asparagine/glutamine sidechain amides is consistent with MD simulations. The measurement of site-specific heteronuclear NOEs is enabled by the use of highly deuterated microcrystalline protein samples in which spin diffusion is reduced in comparison to protonated samples.

Kinetics and efficiency of a methyl-carboxylated 5-Fluorouracil-bovine serum albumin adduct for targeted delivery
Koziol(*), M. J., Sievers(*), T. K., Smuda(*), K., Xiong(*), Y., Müller(*), A., Wojcik(*), F., Steffen(*), A., Dathe, M., Georgieva(*), R.; Bäumler(*), H.
Macromolecular bioscience, 14:428-439

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: 5-Fluorouracil (5-FU) is a clinically well-established anti-cancer drug effectively applied in chemotherapy, mainly for the treatment of breast and colorectal cancer. Substantial disadvantages are adverse effects, arising from serious damage of healthy tissues, and shortcoming pharmacokinetics due to its low molecular weight. A promising approach for improvement of such drugs is their coupling to suitable carriers. Here, a 5-FU adduct, 5-fluorouracil acetate (FUAc) is synthesized and covalently coupled to bovine serum albumin (BSA) as model carrier molecule. On average, 12 molecules FUAc are bound to one BSA. Circular dichriosm (CD)-spectra of BSA and FUAc-BSA are identical, suggesting no significant conformational differences. FUAc-BSA is tested on T-47D and MDA-MB-231 breast cancer cells. Proliferation inhibition of membrane albumin-binding protein (mABP)-expressing T-47D cells by FUAc-BSA is similar to that of 5-FU and only moderate for MDA-MB-231 cells that lack such expression. Therefore, a crucial role of mABP expression in effective cell growth inhibition by FUAc-BSA is assumed.

Towards automatic protein backbone assignment using proton-detected 4D solid-state NMR data
Xiang(*), S., Chevelkov(*), V., Becker(*), S.; Lange, A.
J Biomol NMR, 60:85-90

Tags: Molecular Biophysics (Lange, A.)

Abstract: We introduce an efficient approach for sequential protein backbone assignment based on two complementary proton-detected 4D solid-state NMR experiments that correlate Hi(N)/Ni with CAi/COi or CAi-1/COi-1. The resulting 4D spectra exhibit excellent sensitivity and resolution and are amenable to (semi-)automatic assignment approaches. This strategy allows to obtain sequential connections with high confidence as problems related to peak overlap and multiple assignment possibilities are avoided. Non-uniform sampling schemes were implemented to allow for the acquisition of 4D spectra within a few days. Rather moderate hardware requirements enable the successful demonstration of the method on deuterated type III secretion needles using a 600 MHz spectrometer at a spinning rate of 25 kHz.


Comparison of solid-state dipolar couplings and solution relaxation data provides insight into protein backbone dynamics
Chevelkov, V., Xue(*), Y., Linser, R., Skrynnikov(*), N. R.; Reif, B.
J Am Chem Soc, 132:5015-5017

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Analyses of solution (15)N relaxation data and solid-state (1)H(N)-(15)N dipolar couplings from a small globular protein, alpha-spectrin SH3 domain, produce a surprisingly similar pattern of order parameters. This result suggests that there is little or no ns-mus dynamics throughout most of the sequence and, in particular, in the structured portion of the backbone. At the same time, evidence of ns-mus motions is found in the flexible loops and termini. These findings, corroborated by the MD simulations of alpha-spectrin SH3 in a hydrated crystalline environment and in solution, are consistent with the picture of protein dynamics that has recently emerged from the solution studies employing residual dipolar couplings.

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.

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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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