Research Area C - Publications 2015

Nucl. Acids Res., doi: 10.1093/nar/gkv1517
Nucl. Acids Res., online article

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During protein synthesis, ribosomes become stalled on polyproline-containing sequences, unless they are rescued in archaea and eukaryotes by the initiation factor 5A (a/eIF-5A) and in bacteria by the homologous protein EF-P. While a structure of EF-P bound to the 70S ribosome exists, structural insight into eIF-5A on the 80S ribosome has been lacking. Here we ...

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Angew. Chem. Int. Ed., Volume 55, Issue 4, Pages 1540–1543, DOI: 10.1002/anie.201508713
Angew. Chem. Int. Ed., online article

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Due to its unique role as a hydrogen-bond donor and its positive charge, the guanidine group is an important pharmacophoric group and often used in synthetic ligands. The chemical modification of the guanidine group is often considered to destroy its function. Herein, we show that the N-methylation, N-alkylation, or N-acylation of the guanidine group can be used ...

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Angew. Chem. Int. Ed., Volume 55, Issue, Pages 1535–1539, DOI: 10.1002/anie.201508709
Angew. Chem. Int. Ed., online aticle

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The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies ...

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Oncotarget, 6(39):41884-901, doi: 10.18632/oncotarget.6099
Oncotarget, online article

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Distant metastases arise in 20-30% of patients with squamous cell carcinoma of the head and neck (HNSCC) in the 2 years following treatment. Therapeutic options are limited and the outcome of the patients is poor. The identification of predictive biomarkers of patient at risk for distant metastasis and therapies are urgently needed. We previously identified a ...

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J. Phys. Chem. Lett., 6 (24), pp 5040–5044, DOI: 10.1021/acs.jpclett.5b02467

J. Phys. Chem. Lett., online article

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Spin-state-selective excitation (S3E) experiments allow the selection of individual transitions in a coupled two spin system. We show that in the solid state, the dipole–dipole interaction (DD) between 15N and 1H in a 1H–15N bond and the chemical shift anisotropy (CSA) of 15N in an amide moiety mutually cancel each other for a particular multiplet component at ...

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eLife, 4:e10859. DOI: 10.7554/eLife.10859
eLife, online article

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The cytosolic antiviral innate immune sensor RIG-I distinguishes 5′ tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) ...

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Nature Communications, 6, Article number: 8875, doi:10.1038/ncomms9875

Nature Communications, online article

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Canonical membrane protein biogenesis requires co-translational delivery of ribosome-associated proteins to the Sec translocase and depends on the signal recognition particle (SRP) and its receptor (SR). In contrast, high-throughput delivery of abundant light-harvesting chlorophyll a,b-binding proteins (LHCPs) in chloroplasts to the Alb3 insertase occurs ...

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Molecular Cell, 61,doi:10.1016/j.molcel.2015.10.019

Molecular Cell , online article

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Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of our current arsenal of clinically relevant ...

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Molecular Cell, Volume 61, Issue 1, p3–14, http://dx.doi.org/10.1016/j.molcel.2015.10.019
Molecular Cell, online article

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Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of our current arsenal of clinically relevant ...

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Journal of Molecular Biology, Volume 427, Issue 22, Pages 3572–3586, doi:10.1016/j.jmb.2015.09.012

Journal of Molecular Biology, online article

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The association of light chains (LCs) and heavy chains is the basis for functional antibodies that are essential for adaptive immune responses. However, in some cases, LCs and especially fragments consisting of the LC variable (VL) domain are pathologically deposited in fatal aggregation diseases. The two domains of the LC are connected by a highly conserved ...

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Molecular Microbiology, DOI: 10.1111/mmi.13233

Molecular Microbiology, online article

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Synthesis of polyproline proteins leads to translation arrest. To overcome this ribosome stalling effect, bacteria depend on a specialized translation elongation factor P (EF-P), being orthologous and functionally identical to eukaryotic/archaeal elongation factor e/aIF-5A (recently renamed ‘EF5’). EF-P binds to the stalled ribosome between the peptidyl-tRNA ...

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Molecular Cell, Volume 60, Issue 3, p487–499, http://dx.doi.org/10.1016/j.molcel.2015.10.011

Molecular Cell, online article

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The MLE helicase remodels the roX lncRNAs, enabling the lncRNA-mediated assembly of the Drosophila dosage compensation complex. We identified a stable MLE core comprising the DExH helicase module and two auxiliary domains: a dsRBD and an OB-like fold. MLEcore is an unusual DExH helicase that can unwind blunt-ended RNA duplexes and has specificity for uridine ...

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The Journal of Biological Chemistry, 290, 30843-30854 , doi: 10.1074/jbc.M115.693150

The Journal of Biological Chemistry, online article

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Protein kinases are the most prominent group of heat shock protein 90 (Hsp90) clients and are recruited to the molecular chaperone by the kinase-specific cochaperone cell division cycle 37 (Cdc37). The interaction between Hsp90 and nematode Cdc37 is mediated by binding of the Hsp90 middle domain to an N-terminal region of Caenorhabditis elegans Cdc37 (CeCdc37). ...

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Cell Reports, 13, 703–711, http://dx.doi.org/10.1016/j.celrep.2015.09.033

Cell Reports, online article

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The DEAD-box protein DDX6 is a central component of translational repression mechanisms in maternal mRNA storage in oocytes and microRNA-mediated silencing in somatic cells. DDX6 interacts with the CCR4-NOT complex and functions in concert with several post-transcriptional regulators, including Edc3, Pat1, and 4E-T. We show that the conserved CUP-homology domain ...

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European Journal of Nuclear Medicine and Molecular Imaging, Volume 43, Issue 5, pp 953-963, DOI 10.1007/s00259-015-3218-z
European Journal of Nuclear Medicine and Molecular Imaging, online article

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Purpose Integrins are transmembrane receptors responsible for cell–cell adhesion and cell–extracellular matrix binding and play an important role in angiogenesis and tumour metastasis. For this reason, integrins are increasingly used as targets for molecular imaging. Up to now interest has mostly been focused on the integrin subtype αvβ3. However, targeting of ...

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Colloids and Surfaces B: Biointerfaces, Volume 136, Pages 704–711, doi:10.1016/j.colsurfb.2015.10.008

Colloids and Surfaces B: Biointerfaces, online article

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Implant materials require optimal biointegration, including strong and stable cell-material interactions from the early stages of implantation. Ti-based alloys with low elastic modulus are attracting a lot of interest for avoiding stress shielding, but their osseointegration potential is still very low. In this study, we report on how cell adhesion is influenced ...

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Cell Death & Differentiation, 23, 640-653, doi:10.1038/cdd.2015.131
Cell Death & Differentiation, online article

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, ...

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Nature Structural & Molecular Biology, 22, 898–905, doi:10.1038/nsmb.3108

Nature Structural & Molecular Biology, online article

 

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Small heat-shock proteins, including αB-crystallin (αB), play an important part in protein homeostasis, because their ATP-independent chaperone activity inhibits uncontrolled protein aggregation. Mechanistic details of human αB, particularly in its client-bound state, have been elusive so far, owing to the high molecular weight and the heterogeneity of these ...

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Biochimica et Biophysica Acta, doi:10.1016/j.bbamcr.2015.09.034

Biochimica et Biophysica Acta, online article

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The peroxisomal proteins (peroxins) that mediate the import of peroxisomal matrix proteins have been identified. Recently, the purification of a functional peroxisomal translocon has been reported. However, the molecular details of the import pathways and the mechanisms by which the cargo is translocated into the lumen of the organelle are still poorly ...

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Biochimica et Biophysica Acta, http://dx.doi.org/10.1016/j.bbamcr.2015.09.031

Biochimica et Biophysica Acta, online article

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The correct topogenesis of peroxisomal membrane proteins is a crucial step for the formation of functioning peroxisomes. Although this process has been widely studied, the exact mechanism with which it occurs has not yet been fully characterized. Nevertheless, it is generally accepted that peroxisomes employ three proteins – Pex3, Pex19 and Pex16 in mammals – for ...

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JOURNAL OF BIOLOGICAL CHEMISTRY, VOLUME 290, NUMBER 48, DOI 10.1074/jbc.M115.675215

JOURNAL OF BIOLOGICAL CHEMISTRY, online article

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Alzheimer's disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation have been suggested. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators (GSMs). It has been ...

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J. Am. Chem. Soc., 137 (40), pp 12997–13006, DOI: 10.1021/jacs.5b07427

J. Am. Chem. Soc., online article

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The peptide bond formation with the amino acid proline (Pro) on the ribosome is slow, resulting in translational stalling when several Pro have to be incorporated into the peptide. Stalling at poly-Pro motifs is alleviated by the elongation factor P (EF-P). Here we investigate why Pro is a poor substrate and how EF-P catalyzes the reaction. Linear free energy ...

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Nature Structural & Molecular Biology, 22, 767–773, doi:10.1038/nsmb.3086

Nature Structural & Molecular Biology, online article

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The signal recognition particle (SRP) recognizes signal sequences of nascent polypeptides and targets ribosome–nascent chain complexes to membrane translocation sites. In eukaryotes, translating ribosomes are slowed down by the Alu domain of SRP to allow efficient targeting. In prokaryotes, however, little is known about the structure and function of Alu ...

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Chem. Eur. J. 2015, 21, 15148 – 15152, DOI: 10.1002/chem.201501600

Chem. Eur. J.,online article

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Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven ...

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Journal of Biomolecular NMR, Volume 63, Issue 1, pp 1-8, DOI 10.1007/s10858-015-9981-0

J Biomol NMR, online article

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NMR studies of multi-domain protein complexes provide unique insight into their molecular interactions and dynamics in solution. For large proteins domain-selective isotope labeling is desired to reduce signal overlap, but available methods require extensive optimization and often give poor ligation yields. We present an optimized strategy for segmental labeling ...

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eLife, 4, e07432, DOI: http://dx.doi.org/10.7554/eLife.07432

eLife, online article

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Swi2/Snf2 ATPases remodel substrates such as nucleosomes and transcription complexes to control a wide range of DNA-associated processes, but detailed structural information on the ATP-dependent remodeling reactions is largely absent. The single subunit remodeler Mot1 (modifier of transcription 1) dissociates TATA box-binding protein (TBP):DNA complexes, offering ...

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Angew. Chem. Int. Ed. 2015, 54, 12472 –12478, DOI: 10.1002/anie.201503184

Angew. Chem. Int. Ed., online article

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To shed light on cell-adhesion-related molecular pathways, synthetic cells offer the unique advantage of a well-controlled model system with reduced molecular complexity. Herein, we show that liposomes with the reconstituted platelet integrin αIIbβ3 as the adhesion-mediating transmembrane protein are a functional minimal cell model for studying cellular adhesion ...

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Nature, 524, 54–58, doi:10.1038/nature14865

Nature, online article

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The eukaryotic exosome is a conserved RNA-degrading complex that functions in RNA surveillance, turnover and processing. How the same machinery can either completely degrade or precisely trim RNA substrates has long remained unexplained. Here we report the crystal structures of a yeast nuclear exosome containing the 9-subunit core, the 3′–5′ RNases Rrp44 and ...

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J. Med. Chem., 2015, 58 (16), pp 6359–6367, DOI: 10.1021/acs.jmedchem.5b00102

J. Med. Chem., online article

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Human melanocortin receptors (hMCRs) have been challenging targets to develop ligands that are explicitly selective for each of their subtypes. To modulate the conformational preferences of the melanocortin ligands and improve the biofunctional agonist/antagonist activities and selectivities, we have applied a backbone N-methylation approach on ...

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Biochemical Journal, 469 (3) 367-374, DOI: 10.1042/BJ20150373

Biochemical Journal, online article

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The identification of the essential bacterial second messenger cyclic-di-AMP (c-di-AMP) synthesized by the DNA-integrity scanning protein A (DisA) has opened up a new and emerging field in bacterial signalling. To further analyse the diadenylate cyclase (DAC) reaction catalysed by the DAC domains of DisA, we crystallized Thermotoga maritima DisA in the presence ...

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PNAS, vol. 112 no. 28,  8614–8619, doi: 10.1073/pnas.1504648112

PNAS, online article

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The Caenorhabditis elegans germ-line development defective (GLD)-2–GLD-3 complex up-regulates the expression of genes required for meiotic progression. GLD-2–GLD-3 acts by extending the short poly(A) tail of germ-line–specific mRNAs, switching them from a dormant state into a translationally active state. GLD-2 is a cytoplasmic noncanonical poly(A) polymerase ...

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The Journal of Biological Chemistry, VOL. 290, NO. 36, pp. 22111–22126, doi: 10.1074/jbc.M115.675066 

The Journal of Biological Chemistry, online article

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The IL-4-inducing principle from Schistosoma mansoni eggs (IPSE/α-1), the major secretory product of eggs from the parasitic worm S. mansoni, efficiently triggers basophils to release the immunomodulatory key cytokine interleukin-4. Activation by IPSE/α-1 requires the presence of IgE on the basophils, but the detailed molecular mechanism underlying activation is ...

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Structure, Volume 23, Issue 7, p1336–1343, http://dx.doi.org/10.1016/j.str.2015.04.018

Structure, online article

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Ski7 is a cofactor of the cytoplasmic exosome in budding yeast, functioning in both mRNA turnover and non-stop decay (NSD), a surveillance pathway that degrades faulty mRNAs lacking a stop codon. The C-terminal region of Ski7 (Ski7C) shares overall sequence similarity with the translational GTPase (trGTPase) Hbs1, but whether Ski7 has retained the properties of a ...

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Bioessays, 2015, DOI: 10.1002/bies.201500033, published on 08.06.2015
Bioessays, online article
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RNA binding proteins (RBPs) are key factors for the regulation of gene expression by binding to cis elements, i.e. short sequence motifs in RNAs. Recent studies demonstrate that cooperative binding of multiple RBPs is important for the sequence-specific recognition of RNA and thereby enables the regulation of diverse biological activities by a limited set of ...

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Acta Cryst., 2015, http://dx.doi.org/10.1107/S2053230X15007566, F71, 752-757 published on 08.06.2015
Acta Cryst., online article
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Together with the Rad50 ATPase, the Mre11 nuclease forms an evolutionarily conserved protein complex that plays a central role in the repair of DNA double-strand breaks (DSBs). Mre11-Rad50 detects and processes DNA ends, and has functions in the tethering as well as the signalling of DSBs. The Mre11 dimer can bind one or two DNA ends or hairpins, and processes ...

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Molecular Cell, 2015, DOI: http://dx.doi.org/10.1016/j.molcel.2015.04.014, Volume 58, Issue 5, p832–844 published on 04.06.2015
Molecular Cell, online article
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The increase in multi-drug-resistant bacteria is limiting the effectiveness of currently approved antibiotics, leading to a renewed interest in antibiotics with distinct chemical scaffolds. We have solved the structures of the Thermus thermophilus 70S ribosome with A-, P-, and E-site tRNAs bound and in complex with either the aminocyclitol-containing antibiotic ...

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