TY - THES A1 - Zhang, Gong T1 - Transient ribosomal attenuation as a generic mechanism to coordinate protein biosynthesis and biogenesis Y1 - 2009 CY - Potsdam 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 - Czech, Andreas A1 - Fedyunin, Ivan A1 - Zhang, Gong A1 - Ignatova, Zoya T1 - Silent mutations in sight : co-variations in tRNA abundance as a key to unravel consequences of silent mutations N2 - Mutations that alter the amino acid sequence are known to potentially exert deleterious effects on protein function, whereas substitutions of nucleotides without amino acid change are assumed to be neutral for the protein's functionality. However, cumulative evidence suggests that synonymous substitutions might also induce phenotypic variability by affecting splicing accuracy, translation fidelity, and conformation and function of proteins. tRNA isoacceptors mediate the translation of codons to amino acids, and asymmetric tRNA abundance causes variations in the rate of translation of each single triplet. Consequently, the effect of a silent point mutation in the coding region could be significant due to differential abundances of the cognate tRNA(s), emphasizing the importance of precise assessment of tRNA composition. Here, we provide an overview of the methods used to quantitatively determine the concentrations of tRNA species and discuss synonymous mutations in the context of tRNA composition of the cell, thus providing a new twist on the detrimental impact of the silent mutations. Y1 - 2010 UR - http://www.rsc.org/Publishing/Journals/mb/index.asp U6 - https://doi.org/10.1039/C004796c SN - 1742-206X 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 - Borwankar, Tejas A1 - Roethlein, Christoph A1 - Zhang, Gong A1 - Techen, Anne A1 - Dosche, Carsten A1 - Ignatova, Zoya T1 - Natural osmolytes remodel the aggregation pathway of mutant huntingtin exon 1 JF - Biochemistry N2 - In response to stress small organic compounds termed osmolytes are ubiquitously accumulated in all cell types to regulate the intracellular solvent quality and to counteract the deleterious effect on the stability and function of cellular proteins. Given the evidence that destabilization of the native state of a protein either by mutation or by environmental changes triggers the aggregation in the neurodegenerative pathologies, the modulation of the intracellular solute composition with osmolytes is an attractive strategy to stabilize an aggregating protein. Here we report the effect of three natural osmolytes on the in vivo and in vitro aggregation landscape of huntingtin exon 1 implicated in the Huntington's disease. Trimethylamine N-oxide (TMAO) and proline redirect amyloid fibrillogenesis of the pathological huntingtin exon 1 to nonamyloidogenic amorphous assemblies via two dissimilar molecular mechanisms. TMAO causes a rapid formation of bulky amorphous aggregates with minimally exposed surface area, whereas proline solubilizes the monomer and suppresses the accumulation of early transient aggregates. Conversely, glycine betaine enhances fibrillization in a fashion reminiscent of the genesis of functional amyloids. Strikingly, none of the natural osmolytes can completely abrogate the aggregate formation; however, they redirect the amyloidogenesis into alternative, nontoxic aggregate species. Our study reveals new insights into the complex interactions of osmoprotectants with polyQaggregates. Y1 - 2011 U6 - https://doi.org/10.1021/bi1018368 SN - 0006-2960 VL - 50 IS - 12 SP - 2048 EP - 2060 PB - American Chemical Society CY - Washington 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 - 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 - JOUR A1 - Fedyunin, Ivan A1 - Lehnhardt, Lothar A1 - Böhmer, Nadine A1 - Kaufmann, Paul A1 - Zhang, Gong A1 - Ignatov, Zoya T1 - tRNA concentration fine tunes protein solubility Y1 - 2012 UR - http://www.sciencedirect.com/science/article/pii/S0014579312005807 ER - TY - JOUR A1 - Hinz, Justyna A1 - Lehnhardt, Lothar A1 - Zakrzewski, Silke A1 - Zhang, Gong A1 - Ignatova, Zoya T1 - Polyglutamine expansion alters the dynamics and molecular architecture of aggregates in dentatorubropallidoluysian atrophy JF - The journal of biological chemistry N2 - Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration. Y1 - 2012 U6 - https://doi.org/10.1074/jbc.M111.318915 SN - 0021-9258 VL - 287 IS - 3 SP - 2068 EP - 2078 PB - American Society for Biochemistry and Molecular Biology CY - Bethesda ER -