TY - JOUR A1 - Zhang, Gong A1 - Lukoszek, Radoslaw A1 - Müller-Röber, Bernd A1 - Ignatova, Zoya T1 - Different sequence signatures in the upstream regions of plant and animal tRNA genes shape distinct modes of regulation JF - Nucleic acids research N2 - In eukaryotes, the transcription of tRNA genes is initiated by the concerted action of transcription factors IIIC (TFIIIC) and IIIB (TFIIIB) which direct the recruitment of polymerase III. While TFIIIC recognizes highly conserved, intragenic promoter elements, TFIIIB binds to the non-coding 5'-upstream regions of the tRNA genes. Using a systematic bioinformatic analysis of 11 multicellular eukaryotic genomes we identified a highly conserved TATA motif followed by a CAA-motif in the tRNA upstream regions of all plant genomes. Strikingly, the 5'-flanking tRNA regions of the animal genomes are highly heterogeneous and lack a common conserved sequence signature. Interestingly, in the animal genomes the tRNA species that read the same codon share conserved motifs in their upstream regions. Deep-sequencing analysis of 16 human tissues revealed multiple splicing variants of two of the TFIIIB subunits, Bdp1 and Brf1, with tissue-specific expression patterns. These multiple forms most likely modulate the TFIIIB-DNA interactions and explain the lack of a uniform signature motif in the tRNA upstream regions of animal genomes. The anticodon-dependent 5'-flanking motifs provide a possible mechanism for independent regulation of the tRNA transcription in various human tissues. Y1 - 2011 U6 - https://doi.org/10.1093/nar/gkq1257 SN - 0305-1048 VL - 39 IS - 8 SP - 3331 EP - 3339 PB - Oxford Univ. Press CY - Oxford ER - TY - GEN A1 - Zhang, Gong A1 - Ignatova, Zoya T1 - Generic algorithm to predict the speed of translational elongation : implications for protein biogenesis N2 - Synonymous codon usage and variations in the level of isoaccepting tRNAs exert a powerful selective force on translation fidelity. We have developed an algorithm to evaluate the relative rate of translation which allows large-scale comparisons of the non-uniform translation rate on the protein biogenesis. Using the complete genomes of Escherichia coli and Bacillus subtilis we show that stretches of codons pairing to minor tRNAs form putative sites to locally attenuate translation; thereby the tendency is to cluster in near proximity whereas long contiguous stretches of slow-translating triplets are avoided. The presence of slow-translating segments positively correlates with the protein length irrespective of the protein abundance. The slow-translating clusters are predominantly located down-stream of the domain boundaries presumably to fine-tune translational accuracy with the folding fidelity of multidomain proteins. Translation attenuation patterns at highly structurally and functionally conserved domains are preserved across the species suggesting a concerted selective pressure on the codon selection and species-specific tRNA abundance in these regions. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - paper 132 Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus-45007 ER - TY - JOUR A1 - Zhang, Gong A1 - Ignatova, Zoya T1 - Folding at the birth of the nascent chain: coordinating translation with co-translational folding JF - Current opinion in structural biology : review of all advances ; evaluation of key references ; comprehensive listing of papers N2 - In the living cells, the folding of many proteins is largely believed to begin co-translationally, during their biosynthesis at the ribosomes. In the ribosomal tunnel, the nascent peptide may establish local interactions and stabilize alpha-helical structures. Long-range contacts are more likely outside the ribosomes after release of larger segments of the nascent chain. Examples suggest that domains can attain native-like structure on the ribosome with and without population of folding intermediates. The co-translational folding is limited by the speed of the gradual extrusion of the nascent peptide which imposes conformational restraints on its folding landscape. Recent experimental and in silico modeling studies indicate that translation kinetics fine-tunes co-translational folding by providing a time delay for sequential folding of distinct portions of the nascent chain. Y1 - 2011 U6 - https://doi.org/10.1016/j.sbi.2010.10.008 SN - 0959-440X VL - 21 IS - 1 SP - 25 EP - 31 PB - Elsevier CY - London ER - TY - JOUR A1 - Zhang, Gong A1 - Hubalewska, Magdalena A1 - Ignatova, Zoya T1 - Transient ribosomal attenuation coordinates protein synthesis and co-translational folding N2 - Clustered codons that pair to low-abundance tRNA isoacceptors can form slow-translating regions in the mRNA and cause transient ribosomal arrest. We report that folding efficiency of the Escherichia coli multidomain protein Sufl can be severely perturbed by alterations in ribosome-mediated translational attenuation. Such alterations were achieved by global acceleration of the translation rate with tRNA excess in vitro or by synonymous substitutions to codons with highly abundant tRNAs both in vitro and in vivo. Conversely, the global slow-down of the translation rate modulated by low temperature suppresses the deleterious effect of the altered translational attenuation pattern. We propose that local discontinuous translation temporally separates the translation of segments of the peptide chain and actively coordinates their co-translational folding. Y1 - 2009 UR - http://www.nature.com/nsmb/ U6 - https://doi.org/10.1038/Nsmb.1554 SN - 1545-9985 ER - TY - JOUR A1 - Zhang, Gong A1 - Fedyunin, Ivan A1 - Miekley, Oskar A1 - Valleriani, Angelo A1 - Moura, Alessandro A1 - Ignatova, Zoya T1 - Global and local depletion of ternary complex limits translational elongation N2 - The translation of genetic information according to the sequence of the mRNA template occurs with high accuracy and fidelity. Critical events in each single step of translation are selection of transfer RNA (tRNA), codon reading and tRNA-regeneration for a new cycle. We developed a model that accurately describes the dynamics of single elongation steps, thus providing a systematic insight into the sensitivity of the mRNA translation rate to dynamic environmental conditions. Alterations in the concentration of the aminoacylated tRNA can transiently stall the ribosomes during translation which results, as suggested by the model, in two outcomes: either stress-induced change in the tRNA availability triggers the premature termination of the translation and ribosomal dissociation, or extensive demand for one tRNA species results in a competition between frameshift to an aberrant open-reading frame and ribosomal drop-off. Using the bacterial Escherichia coli system, we experimentally draw parallels between these two possible mechanisms. Y1 - 2010 UR - http://nar.oxfordjournals.org/ U6 - https://doi.org/10.1093/Nar/Gkq196 SN - 0305-1048 ER - TY - JOUR A1 - Zhang, Gong A1 - Fedyunin, Ivan A1 - Kirchner, Sebastian A1 - Xiao, Chuanle A1 - Valleriani, Angelo A1 - Ignatova, Zoya T1 - FANSe: an accurate algorithm for quantitative mapping of large scale sequencing reads JF - Nucleic acids research N2 - The most crucial step in data processing from high-throughput sequencing applications is the accurate and sensitive alignment of the sequencing reads to reference genomes or transcriptomes. The accurate detection of insertions and deletions (indels) and errors introduced by the sequencing platform or by misreading of modified nucleotides is essential for the quantitative processing of the RNA-based sequencing (RNA-Seq) datasets and for the identification of genetic variations and modification patterns. We developed a new, fast and accurate algorithm for nucleic acid sequence analysis, FANSe, with adjustable mismatch allowance settings and ability to handle indels to accurately and quantitatively map millions of reads to small or large reference genomes. It is a seed-based algorithm which uses the whole read information for mapping and high sensitivity and low ambiguity are achieved by using short and non-overlapping reads. Furthermore, FANSe uses hotspot score to prioritize the processing of highly possible matches and implements modified Smith-Watermann refinement with reduced scoring matrix to accelerate the calculation without compromising its sensitivity. The FANSe algorithm stably processes datasets from various sequencing platforms, masked or unmasked and small or large genomes. It shows a remarkable coverage of low-abundance mRNAs which is important for quantitative processing of RNA-Seq datasets. Y1 - 2012 U6 - https://doi.org/10.1093/nar/gks196 SN - 0305-1048 VL - 40 IS - 11 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Yuryev, Ruslan A1 - Kasche, Volker A1 - Ignatova, Zoya A1 - Galunsky, Boris T1 - Improved A. faecalis penicillin amidase mutant retains the thermodynamic and pH stability of the wild type enzyme N2 - Penicillin amidase from Alacaligenes faecalis is an attractive biocatalyst for hydrolysis of penicillin G for production of 6-aminopenicillanic acid, which is used in the synthesis of semi-synthetic beta-lactam antibiotics. Recently a mutant of this enzyme with extended C-terminus of the A-chain comprising parts of the connecting linker peptide was constructed. Its turnover number for the hydrolysis of penicillin G was 140 s(-1), about twice of the value for the wild-type enzyme (80 s(-1)). At the same time the specificity constant was improved about three-fold. The wild- type and the mutant enzymes showed similar pH stability suggesting that the linker peptide fragment covalently attached to the A-chain does not alter the electrostatic interactions in the protein core. Although the global stability of A. faecalis wild-type enzyme and the T206GS213G variant does not differ, the presence of the linker fragment stabilizes the domains interface, as evidenced by the monophasic transition of the mutant enzyme from folded to unfolded state during urea-induced denaturation. The high stability and activity of the mutant enzyme provides a rationale to use it as a biocatalyst in the industrial processes, where the enzyme must be more robust to fluctuations in the operational conditions. Y1 - 2010 UR - http://springerlink.metapress.com/content/1573-4943/ U6 - https://doi.org/10.1007/s10930-010-9238-4 SN - 1572-3887 ER - TY - JOUR A1 - Weissenborn, Christine A1 - Ignatov, Tanja A1 - Ochel, Hans-Joachim A1 - Costa, Serban Dan A1 - Zenclussen, Ana Claudia A1 - Ignatova, Zoya A1 - Ignatov, Atanas T1 - GPER functions as a tumor suppressor in triple-negative breast cancer cells JF - Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft N2 - We investigated the role of GPER as a potential tumor suppressor in triple-negative breast cancer cells MDA-MB-231 and MDA-MB-468 using cell cycle analysis and apoptosis assay. The constitutive activity of GPER was investigated. GPER-specific activation with G-1 agonist inhibited breast cancer cell growth in concentration-dependent manner via induction of the cell cycle arrest in G2/M phase, enhanced phosphorylation of histone H3 and caspase-3-mediated apoptosis. Analysis of the methylation status of the GPER promoter in the triple-negative breast cancer cells and in tissues derived from breast cancer patients revealed that GPER amount is regulated by epigenetic mechanisms and GPER expression is inactivated by promoter methylation. Furthermore, GPER expression was induced by stress factors, such as radiation, and GPER amount inversely correlated with the p53 expression level. Overall, our results establish the protective role in breast cancer tumorigenesis, and the cell surface expression of GPER makes it an excellent potential therapeutic target for triple-negative breast cancer. KW - GPER KW - GPR30 KW - Breast cancer KW - Tumor suppression KW - TNBC Y1 - 2014 U6 - https://doi.org/10.1007/s00432-014-1620-8 SN - 0171-5216 SN - 1432-1335 VL - 140 IS - 5 SP - 713 EP - 723 PB - Springer CY - New York ER - TY - JOUR A1 - Varshney, Nishant Kumar A1 - Kumar, R. Suresh A1 - Ignatova, Zoya A1 - Prabhune, Asmita A1 - Pundle, Archana A1 - Dodson, Eleanor A1 - Suresh, C. G. T1 - Crystallization and X-ray structure analysis of a thermostable penicillin G acylase from Alcaligenes faecalis JF - Acta crystallographica : Section F, Structural biology communications N2 - The enzyme penicillin G acylase (EC 3.5.1.11) catalyzes amide-bond cleavage in benzylpenicillin (penicillin G) to yield 6-aminopenicillanic acid, an intermediate chemical used in the production of semisynthetic penicillins. A thermostable penicillin G acylase from Alcaligenes faecalis (AfPGA) has been crystallized using the hanging-drop vapour-diffusion method in two different space groups: C2221, with unit-cell parameters a = 72.9, b = 86.0, c = 260.2 angstrom, and P41212, with unit-cell parameters a = b = 85.6, c = 298.8 angstrom. Data were collected at 293 K and the structure was determined using the molecular-replacement method. Like other penicillin acylases, AfPGA belongs to the N-terminal nucleophilic hydrolase superfamily, has undergone post-translational processing and has a serine as the N-terminal residue of the beta-chain. A disulfide bridge has been identified in the structure that was not found in the other two known penicillin G acylase structures. The presence of the disulfide bridge is perceived to be one factor that confers higher stability to this enzyme. KW - thermostability KW - disulfide bridges KW - Ntn hydrolases KW - orthorhombic form KW - tetragonal form KW - calcium binding Y1 - 2012 U6 - https://doi.org/10.1107/S1744309111053930 SN - 1744-3091 VL - 68 IS - 3 SP - 273 EP - 277 PB - Wiley-Blackwell CY - Malden ER - TY - JOUR A1 - Valleriani, Angelo A1 - Zhang, Gong A1 - Nagar, Apoorva A1 - Ignatova, Zoya A1 - Lipowsky, Reinhard T1 - Length-dependent translation of messenger RNA by ribosomes JF - Physical review : E, Statistical, nonlinear and soft matter physics N2 - A simple measure for the efficiency of protein synthesis by ribosomes is provided by the steady state amount of protein per messenger RNA (mRNA), the so-called translational ratio, which is proportional to the translation rate. Taking the degradation of mRNA into account, we show theoretically that both the translation rate and the translational ratio decrease with increasing mRNA length, in agreement with available experimental data for the prokaryote Escherichia coli. We also show that, compared to prokaryotes, mRNA degradation in eukaryotes leads to a less rapid decrease of the translational ratio. This finding is consistent with the fact that, compared to prokaryotes, eukaryotes tend to have longer proteins. Y1 - 2011 U6 - https://doi.org/10.1103/PhysRevE.83.042903 SN - 1539-3755 VL - 83 IS - 4 PB - American Physical Society CY - College Park ER - TY - JOUR A1 - Valleriani, Angelo A1 - Ignatova, Zoya A1 - Nagar, Apoorva A1 - Lipowsky, Reinhard T1 - Turnover of messenger RNA : polysome statistics beyond the steady state N2 - The interplay between turnover or degradation and ribosome loading of messenger RNA (mRNA) is studied theoretically using a stochastic model that is motivated by recent experimental results. Random mRNA degradation affects the statistics of polysomes, i.e., the statistics of the number of ribosomes per mRNA as extracted from cells. Since ribosome loading of newly created mRNA chains requires some time to reach steady state, a fraction of the extracted mRNA/ ribosome complexes does not represent steady state conditions. As a consequence, the mean ribosome density obtained from the extracted complexes is found to be inversely proportional to the mRNA length. On the other hand, the ribosome density profile shows an exponential decrease along the mRNA for prokaryotes and becomes uniform in eukaryotic cells. Copyright (C) EPLA, 2010 Y1 - 2010 UR - http://iopscience.iop.org/0295-5075/ U6 - https://doi.org/10.1209/0295-5075/89/58003 SN - 0295-5075 ER - TY - JOUR A1 - Saffert, Paul A1 - Adamla, Frauke A1 - Schieweck, Rico A1 - Atkins, John F. A1 - Ignatova, Zoya T1 - An Expanded CAG Repeat in Huntingtin Causes+1 Frameshifting JF - The journal of biological chemistry N2 - Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the -1 or +1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic +1 frameshift to generate from the CAG repeat a trans-frame AGC repeat-encoded product. This +1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical +1 shift site, UUC C at the 5 end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the +1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The +1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1. KW - aggregation KW - Huntington disease KW - translation KW - translation regulation KW - trinucleotide repeat disease KW - frameshifting KW - seeding Y1 - 2016 U6 - https://doi.org/10.1074/jbc.M116.744326 SN - 0021-9258 SN - 1083-351X VL - 291 SP - 18505 EP - 18513 PB - American Society for Biochemistry and Molecular Biology CY - Bethesda ER - TY - JOUR A1 - Röthlein, Christoph A1 - Miettinen, Markus S. A1 - Ignatova, Zoya T1 - A flexible approach to assess fluorescence decay functions in complex energy transfer systems JF - BMC biophysics N2 - Background: Time-correlated Forster resonance energy transfer (FRET) probes molecular distances with greater accuracy than intensity-based calculation of FRET efficiency and provides a powerful tool to study biomolecular structure and dynamics. Moreover, time-correlated photon count measurements bear additional information on the variety of donor surroundings allowing more detailed differentiation between distinct structural geometries which are typically inaccessible to general fitting solutions. Results: Here we develop a new approach based on Monte Carlo simulations of time-correlated FRET events to estimate the time-correlated single photon counts (TCSPC) histograms in complex systems. This simulation solution assesses the full statistics of time-correlated photon counts and distance distributions of fluorescently labeled biomolecules. The simulations are consistent with the theoretical predictions of the dye behavior in FRET systems with defined dye distances and measurements of randomly distributed dye solutions. We validate the simulation results using a highly heterogeneous aggregation system and explore the conditions to use this tool in complex systems. Conclusion: This approach is powerful in distinguishing distance distributions in a wide variety of experimental setups, thus providing a versatile tool to accurately distinguish between different structural assemblies in highly complex systems. KW - Time resolved FRET KW - Monte-Carlo simulations KW - Complex heterogeneous systems KW - Protein aggregation Y1 - 2015 U6 - https://doi.org/10.1186/s13628-015-0020-z SN - 2046-1682 VL - 8 PB - BioMed Central CY - London ER - TY - GEN A1 - Roethlein, Christoph A1 - Miettinen, Markus S. A1 - Ignatova, Zoya T1 - A flexible approach to assess fluorescence decay functions in complex energy transfer systems T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe 819 N2 - Background: Time-correlated Forster resonance energy transfer (FRET) probes molecular distances with greater accuracy than intensity-based calculation of FRET efficiency and provides a powerful tool to study biomolecular structure and dynamics. Moreover, time-correlated photon count measurements bear additional information on the variety of donor surroundings allowing more detailed differentiation between distinct structural geometries which are typically inaccessible to general fitting solutions. Results: Here we develop a new approach based on Monte Carlo simulations of time-correlated FRET events to estimate the time-correlated single photon counts (TCSPC) histograms in complex systems. This simulation solution assesses the full statistics of time-correlated photon counts and distance distributions of fluorescently labeled biomolecules. The simulations are consistent with the theoretical predictions of the dye behavior in FRET systems with defined dye distances and measurements of randomly distributed dye solutions. We validate the simulation results using a highly heterogeneous aggregation system and explore the conditions to use this tool in complex systems. Conclusion: This approach is powerful in distinguishing distance distributions in a wide variety of experimental setups, thus providing a versatile tool to accurately distinguish between different structural assemblies in highly complex systems. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 819 KW - time resolved FRET KW - Monte-Carlo simulations KW - complex heterogeneous systems KW - protein aggregation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-427557 SN - 1866-8372 IS - 819 ER - TY - JOUR A1 - Roethlein, Christoph A1 - Miettinen, Markus S. A1 - Borwankar, Tejas A1 - Buerger, Joerg A1 - Mielke, Thorsten A1 - Kumke, Michael Uwe A1 - Ignatova, Zoya T1 - Architecture of polyglutamine-containing fibrils from time-resolved fluorescence decay JF - The journal of biological chemistry N2 - The disease risk and age of onset of Huntington disease (HD) and nine other repeat disorders strongly depend on the expansion of CAG repeats encoding consecutive polyglutamines (polyQ) in the corresponding disease protein. PolyQ length-dependent misfolding and aggregation are the hallmarks of CAG pathologies. Despite intense effort, the overall structure of these aggregates remains poorly understood. Here, we used sensitive time-dependent fluorescent decay measurements to assess the architecture of mature fibrils of huntingtin (Htt) exon 1 implicated in HD pathology. Varying the position of the fluorescent labels in the Htt monomer with expanded 51Q (Htt51Q) and using structural models of putative fibril structures, we generated distance distributions between donors and acceptors covering all possible distances between the monomers or monomer dimensions within the polyQ amyloid fibril. Using Monte Carlo simulations, we systematically scanned all possible monomer conformations that fit the experimentally measured decay times. Monomers with four-stranded 51Q stretches organized into five-layered beta-sheets with alternating N termini of the monomers perpendicular to the fibril axis gave the best fit to our data. Alternatively, the core structure of the polyQ fibrils might also be a zipper layer with antiparallel four-stranded stretches as this structure showed the next best fit. All other remaining arrangements are clearly excluded by the data. Furthermore, the assessed dimensions of the polyQ stretch of each monomer provide structural evidence for the observed polyQ length threshold in HD pathology. Our approach can be used to validate the effect of pharmacological substances that inhibit or alter amyloid growth and structure. Y1 - 2014 U6 - https://doi.org/10.1074/jbc.M114.581991 SN - 0021-9258 SN - 1083-351X VL - 289 IS - 39 SP - 26817 EP - 26828 PB - American Society for Biochemistry and Molecular Biology CY - Bethesda ER - TY - JOUR A1 - Puri, Pranav A1 - Wetzel, Collin A1 - Saffert, Paul A1 - Gaston, Kirk W. A1 - Russell, Susan P. A1 - Varela, Juan A. Cordero A1 - van der Vlies, Pieter A1 - Zhang, Gong A1 - Limbach, Patrick A. A1 - Ignatova, Zoya A1 - Poolman, Bert T1 - Systematic identification of tRNAome and its dynamics in Lactococcus lactis JF - Molecular microbiology N2 - Transfer RNAs (tRNAs) through their abundance and modification pattern significantly influence protein translation. Here, we present a systematic analysis of the tRNAome of Lactococcus lactis. Using the next-generation sequencing approach, we identified 40 tRNAs which carry 16 different post-transcriptional modifications as revealed by mass spectrometry analysis. While small modifications are located in the tRNA body, hypermodified nucleotides are mainly present in the anticodon loop, which through wobbling expand the decoding potential of the tRNAs. Using tRNA-based microarrays, we also determined the dynamics in tRNA abundance upon changes in the growth rate and heterologous protein overexpression stress. With a fourfold increase in the growth rate, the relative abundance of tRNAs cognate to low abundance codons decrease, while the tRNAs cognate to major codons remain mostly unchanged. Significant changes in the tRNA abundances are observed upon protein overexpression stress, which does not correlate with the codon usage of the overexpressed gene but rather reflects the altered expression of housekeeping genes. Y1 - 2014 U6 - https://doi.org/10.1111/mmi.12710 SN - 0950-382X SN - 1365-2958 VL - 93 IS - 5 SP - 944 EP - 956 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Miettinen, Markus S. A1 - Monticelli, Luca A1 - Nedumpully-Govindan, Praveen A1 - Knecht, Volker A1 - Ignatova, Zoya T1 - Stable polyglutamine dimers can contain beta-hairpins with interdigitated side chains but not a-helices, alpha-nanotubes, beta-pseudohelices, or steric zippers JF - Biophysical journal N2 - A common thread connecting nine fatal neurodegenerative protein aggregation diseases is an abnormally expanded polyglutamine tract found in the respective proteins. Although the structure of this tract in the large mature aggregates is increasingly well described, its structure in the small early aggregates remains largely unknown. As experimental evidence suggests that the most toxic species along the aggregation pathway are the small early ones, developing strategies to alleviate disease pathology calls for understanding the structure of polyglutamine peptides in the early stages of aggregation. Here, we present a criterion, grounded in available experimental data, that allows for using kinetic stability of dimers to assess whether a given polyglutamine conformer can be on the aggregation path. We then demonstrate that this criterion can be assessed using present-day molecular dynamics simulations. We find that although the a-helical conformer of polyglutamine is very stable, dimers of a-helices lack the kinetic stability necessary to support further oligomerization. Dimers of steric zipper, beta-nanotube, and beta-pseudohelix conformers are also too short-lived to initiate aggregation. The beta-hairpin-containing conformers, instead, invariably form very stable dimers when their side chains are interdigitated. Combining these findings with the implications of recent solid-state NMR data on mature fibrils, we propose a possible pathway for the initial stages of polyglutamine aggregation, in which beta-hairpin-containing conformers act as templates for fibril formation. Y1 - 2014 U6 - https://doi.org/10.1016/j.bpj.2014.02.027 SN - 0006-3495 SN - 1542-0086 VL - 106 IS - 8 SP - 1721 EP - 1728 PB - Cell Press CY - Cambridge ER - TY - CHAP A1 - Miettinen, Markus S. A1 - Monticelli, Luca A1 - Nedumpully-Govindan, Praveen A1 - Knecht, Volker A1 - Ignatova, Zoya T1 - Initiating polyglutamine aggregation - computational clarification of the structural details T2 - Biophysical journal Y1 - 2015 SN - 0006-3495 SN - 1542-0086 VL - 108 IS - 2 SP - 386A EP - 386A PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Miettinen, Markus S. A1 - Knecht, Volker A1 - Monticelli, Luca A1 - Ignatova, Zoya T1 - Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations JF - The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces & biophysical chemistry N2 - Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism. Y1 - 2012 U6 - https://doi.org/10.1021/jp305065c SN - 1520-6106 VL - 116 IS - 34 SP - 10259 EP - 10265 PB - American Chemical Society CY - Washington ER - TY - JOUR A1 - Lukoszek, Radoslaw A1 - Müller-Röber, Bernd A1 - Ignatova, Zoya T1 - Interplay between polymerase II- and polymerase III-assisted expression of overlapping genes JF - FEBS letters : the journal for rapid publication of short reports in molecular biosciences N2 - Up to 15% of the genes in different genomes overlap. This architecture, although beneficial for the genome size, represents an obstacle for simultaneous transcription of both genes. Here we analyze the interference between RNA-polymerase II (Pol II) and RNA-polymerase III (Pol III) when transcribing their target genes encoded on opposing strands within the same DNA fragment in Arabidopsis thaliana. The expression of a Pol II-dependent protein-coding gene negatively correlated with the transcription of a Pol III-dependent, tRNA-coding gene set. We suggest that the architecture of the overlapping genes introduces an additional layer of control of gene expression. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. KW - Gene expression KW - Transcription KW - tRNA KW - Nested and overlapping genes KW - Arabidopsis thaliana Y1 - 2013 U6 - https://doi.org/10.1016/j.febslet.2013.09.033 SN - 0014-5793 SN - 1873-3468 VL - 587 IS - 22 SP - 3692 EP - 3695 PB - Elsevier CY - Amsterdam ER -