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17 pages, 2489 KiB

Open AccessArticle

The Ribosome-Binding Mode of Trichothecene Mycotoxins Rationalizes Their Structure—Activity Relationships

by Weijun Wang, Yan Zhu, Nadine Abraham, Xiu-Zhen Li, Matthew Kimber and Ting Zhou

Int. J. Mol. Sci. 2021, 22(4), 1604; https://doi.org/10.3390/ijms22041604 - 05 Feb 2021

Cited by 23 | Viewed by 2178

Trichothecenes are the most prevalent mycotoxins contaminating cereal grains. Some of them are also considered as the virulence factors of Fusarium head blight disease. However, the mechanism behind the structure-activity relationship for trichothecenes remains unexplained. Filling this information gap is a crucial step [...] Read more.

Trichothecenes are the most prevalent mycotoxins contaminating cereal grains. Some of them are also considered as the virulence factors of Fusarium head blight disease. However, the mechanism behind the structure-activity relationship for trichothecenes remains unexplained. Filling this information gap is a crucial step for developing strategies to manage this large family of mycotoxins in food and feed. Here, we perform an in-depth re-examination of the existing structures of Saccharomyces cerevisiae ribosome complexed with three different trichothecenes. Multiple binding interactions between trichothecenes and 25S rRNA, including hydrogen bonds, nonpolar pi stacking interactions and metal ion coordination interactions, are identified as important binding determinants. These interactions are mainly contributed by the key structural elements to the toxicity of trichothecenes, including the oxygen in the 12,13-epoxide ring and a double bond between C⁹ and C¹⁰. In addition, the C³-OH group also participates in binding. The comparison of three trichothecenes binding to the ribosome, along with their binding pocket architecture, suggests that the substitutions at different positions impact trichothecenes binding in two different patterns. Moreover, the binding of trichothecenes induced conformation changes of several nucleotide bases in 25S rRNA. This then provides a structural framework for understanding the structure-activity relationships apparent in trichothecenes. This study will facilitate the development of strategies aimed at detoxifying mycotoxins in food and feed and at improving the resistance of cereal crops to Fusarium fungal diseases. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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13 pages, 2501 KiB

Open AccessArticle

Arginine Methylation Regulates Ribosome CAR Function

by Kristen Scopino, Carol Dalgarno, Clara Nachmanoff, Daniel Krizanc, Kelly M. Thayer and Michael P. Weir

Int. J. Mol. Sci. 2021, 22(3), 1335; https://doi.org/10.3390/ijms22031335 - 29 Jan 2021

Cited by 5 | Viewed by 2142

Abstract

The ribosome CAR interaction surface is hypothesized to provide a layer of translation regulation through hydrogen-bonding to the +1 mRNA codon that is next to enter the ribosome A site during translocation. The CAR surface consists of three residues, 16S/18S rRNA C1054, A1196 [...] Read more.

The ribosome CAR interaction surface is hypothesized to provide a layer of translation regulation through hydrogen-bonding to the +1 mRNA codon that is next to enter the ribosome A site during translocation. The CAR surface consists of three residues, 16S/18S rRNA C1054, A1196 (E. coli 16S numbering), and R146 of yeast ribosomal protein Rps3. R146 can be methylated by the Sfm1 methyltransferase which is downregulated in stressed cells. Through molecular dynamics analysis, we show here that methylation of R146 compromises the integrity of CAR by reducing the cation-pi stacking of the R146 guanidinium group with A1196, leading to reduced CAR hydrogen-bonding with the +1 codon. We propose that ribosomes assembled under stressed conditions have unmethylated R146, resulting in elevated CAR/+1 codon interactions, which tunes translation levels in response to the altered cellular context. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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22 pages, 3793 KiB

Open AccessCommunication

Cooperativity between the Ribosome-Associated Chaperone Ssb/RAC and the Ubiquitin Ligase Ltn1 in Ubiquitination of Nascent Polypeptides

by Arnab Ghosh and Natalia Shcherbik

Int. J. Mol. Sci. 2020, 21(18), 6815; https://doi.org/10.3390/ijms21186815 - 17 Sep 2020

Cited by 4 | Viewed by 3228

Abstract

Eukaryotic cells have evolved multiple mechanisms to detect and eliminate aberrant polypeptides. Co-translational protein surveillance systems play an important role in these mechanisms. These systems include ribosome-associated protein quality control (RQC) that detects aberrant nascent chains stalled on ribosomes and promotes their ubiquitination [...] Read more.

Eukaryotic cells have evolved multiple mechanisms to detect and eliminate aberrant polypeptides. Co-translational protein surveillance systems play an important role in these mechanisms. These systems include ribosome-associated protein quality control (RQC) that detects aberrant nascent chains stalled on ribosomes and promotes their ubiquitination and degradation by the proteasome, and ribosome-associated chaperone Ssb/RAC, which ensures correct nascent chain folding. Despite the known function of RQC and Ssb/ribosome-associated complex (RAC) in monitoring the quality of newly generated polypeptides, whether they cooperate during initial stages of protein synthesis remains unexplored. Here, we provide evidence that Ssb/RAC and the ubiquitin ligase Ltn1, the major component of RQC, display genetic and functional cooperativity. Overexpression of Ltn1 rescues growth suppression of the yeast strain-bearing deletions of SSB genes during proteotoxic stress. Moreover, Ssb/RAC promotes Ltn1-dependent ubiquitination of nascent chains associated with 80S ribosomal particles but not with translating ribosomes. Consistent with this finding, quantitative western blot analysis revealed lower levels of Ltn1 associated with 80S ribosomes and with free 60S ribosomal subunits in the absence of Ssb/RAC. We propose a mechanism in which Ssb/RAC facilitates recruitment of Ltn1 to ribosomes, likely by detecting aberrations in nascent chains and leading to their ubiquitination and degradation. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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14 pages, 2098 KiB

Open AccessArticle

Ribosomal RNA Modulates Aggregation of the Podospora Prion Protein HET-s

by Yanhong Pang, Petar Kovachev and Suparna Sanyal

Int. J. Mol. Sci. 2020, 21(17), 6340; https://doi.org/10.3390/ijms21176340 - 01 Sep 2020

Cited by 2 | Viewed by 2648

Abstract

The role of the nucleic acids in prion aggregation/disaggregation is becoming more and more evident. Here, using HET-s prion from fungi Podospora anserina (P. anserina) as a model system, we studied the role of RNA, particularly of different domains of the [...] Read more.

The role of the nucleic acids in prion aggregation/disaggregation is becoming more and more evident. Here, using HET-s prion from fungi Podospora anserina (P. anserina) as a model system, we studied the role of RNA, particularly of different domains of the ribosomal RNA (rRNA), in its aggregation process. Our results using Rayleigh light scattering, Thioflavin T (ThT) binding, transmission electron microscopy (TEM) and cross-seeding assay show that rRNA, in particular the domain V of the major rRNA from the large subunit of the ribosome, substantially prevents insoluble amyloid and amorphous aggregation of the HET-s prion in a concentration-dependent manner. Instead, it facilitates the formation of the soluble oligomeric “seeds”, which are capable of promoting de novo HET-s aggregation. The sites of interactions of the HET-s prion protein on domain V rRNA were identified by primer extension analysis followed by UV-crosslinking, which overlap with the sites previously identified for the protein-folding activity of the ribosome (PFAR). This study clarifies a missing link between the rRNA-based PFAR and the mode of propagation of the fungal prions. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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Review

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14 pages, 746 KiB

Open AccessReview

The rDNA Loci—Intersections of Replication, Transcription, and Repair Pathways

by Ivana Goffová and Jiří Fajkus

Int. J. Mol. Sci. 2021, 22(3), 1302; https://doi.org/10.3390/ijms22031302 - 28 Jan 2021

Cited by 16 | Viewed by 4026

Abstract

Genes encoding ribosomal RNA (rDNA) are essential for cell survival and are particularly sensitive to factors leading to genomic instability. Their repetitive character makes them prone to inappropriate recombinational events arising from collision of transcriptional and replication machineries, resulting in unstable rDNA copy [...] Read more.

Genes encoding ribosomal RNA (rDNA) are essential for cell survival and are particularly sensitive to factors leading to genomic instability. Their repetitive character makes them prone to inappropriate recombinational events arising from collision of transcriptional and replication machineries, resulting in unstable rDNA copy numbers. In this review, we summarize current knowledge on the structure and organization of rDNA, its role in sensing changes in the genome, and its linkage to aging. We also review recent findings on the main factors involved in chromatin assembly and DNA repair in the maintenance of rDNA stability in the model plants Arabidopsis thaliana and the moss Physcomitrella patens, providing a view across the plant evolutionary tree. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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11 pages, 1329 KiB

Open AccessReview

Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease

by Mayuresh Anant Sarangdhar and Ramanjaneyulu Allam

Int. J. Mol. Sci. 2021, 22(3), 1287; https://doi.org/10.3390/ijms22031287 - 28 Jan 2021

Cited by 21 | Viewed by 4569

Abstract

Protein synthesis is a highly complex process executed by well-organized translation machinery. Ribosomes, tRNAs and mRNAs are the principal components of this machinery whereas RNA binding proteins and ribosome interacting partners act as accessory factors. Angiogenin (ANG)—Ribonuclease inhibitor (RNH1) system is one such [...] Read more.

Protein synthesis is a highly complex process executed by well-organized translation machinery. Ribosomes, tRNAs and mRNAs are the principal components of this machinery whereas RNA binding proteins and ribosome interacting partners act as accessory factors. Angiogenin (ANG)—Ribonuclease inhibitor (RNH1) system is one such accessory part of the translation machinery that came into focus afresh due to its unconventional role in the translation. ANG is conventionally known for its ability to induce blood vessel formation and RNH1 as a “sentry” to protect RNAs from extracellular RNases. However, recent studies suggest them to be important in translation regulation. During cell homeostasis, ANG in the nucleus promotes rRNA transcription. While under stress, ANG translocates to the cytosol and cleaves tRNA into fragments which inhibit ribosome biogenesis and protein synthesis. RNH1, which intimately interacts with ANG to inhibit its ribonucleolytic activity, can also bind to the 40S ribosomes and control translation by yet to be known mechanisms. Here, we review recent advancement in the knowledge of translation regulation by the ANG-RNH1 system. We also gather information about this system in cell homeostasis as well as in pathological conditions such as cancer and ribosomopathies. Additionally, we discuss the future research directions and therapeutic potential of this system. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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19 pages, 9709 KiB

Open AccessReview

Non-Coding RNA-Driven Regulation of rRNA Biogenesis

by Eleni G. Kaliatsi, Nikoleta Giarimoglou, Constantinos Stathopoulos and Vassiliki Stamatopoulou

Int. J. Mol. Sci. 2020, 21(24), 9738; https://doi.org/10.3390/ijms21249738 - 20 Dec 2020

Cited by 12 | Viewed by 4991

Abstract

Ribosomal RNA (rRNA) biogenesis takes place in the nucleolus, the most prominent condensate of the eukaryotic nucleus. The proper assembly and integrity of the nucleolus reflects the accurate synthesis and processing of rRNAs which in turn, as major components of ribosomes, ensure the [...] Read more.

Ribosomal RNA (rRNA) biogenesis takes place in the nucleolus, the most prominent condensate of the eukaryotic nucleus. The proper assembly and integrity of the nucleolus reflects the accurate synthesis and processing of rRNAs which in turn, as major components of ribosomes, ensure the uninterrupted flow of the genetic information during translation. Therefore, the abundant production of rRNAs in a precisely functional nucleolus is of outmost importance for the cell viability and requires the concerted action of essential enzymes, associated factors and epigenetic marks. The coordination and regulation of such an elaborate process depends on not only protein factors, but also on numerous regulatory non-coding RNAs (ncRNAs). Herein, we focus on RNA-mediated mechanisms that control the synthesis, processing and modification of rRNAs in mammals. We highlight the significance of regulatory ncRNAs in rRNA biogenesis and the maintenance of the nucleolar morphology, as well as their role in human diseases and as novel druggable molecular targets. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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13 pages, 1136 KiB

Open AccessReview

Phylogenetic Utility of rRNA ITS2 Sequence-Structure under Functional Constraint

by Wei Zhang, Wen Tian, Zhipeng Gao, Guoli Wang and Hong Zhao

Int. J. Mol. Sci. 2020, 21(17), 6395; https://doi.org/10.3390/ijms21176395 - 03 Sep 2020

Cited by 22 | Viewed by 3861

Abstract

The crucial function of the internal transcribed spacer 2 (ITS2) region in ribosome biogenesis depends on its secondary and tertiary structures. Despite rapidly evolving, ITS2 is under evolutionary constraints to maintain the specific secondary structures that provide functionality. A link between function, structure [...] Read more.

The crucial function of the internal transcribed spacer 2 (ITS2) region in ribosome biogenesis depends on its secondary and tertiary structures. Despite rapidly evolving, ITS2 is under evolutionary constraints to maintain the specific secondary structures that provide functionality. A link between function, structure and evolution could contribute an understanding to each other and recently has created a growing point of sequence-structure phylogeny of ITS2. Here we briefly review the current knowledge of ITS2 processing in ribosome biogenesis, focusing on the conservative characteristics of ITS2 secondary structure, including structure form, structural motifs, cleavage sites, and base-pair interactions. We then review the phylogenetic implications and applications of this structure information, including structure-guiding sequence alignment, base-pair mutation model, and species distinguishing. We give the rationale for why incorporating structure information into tree construction could improve reliability and accuracy, and some perspectives of bioinformatics coding that allow for a meaningful evolutionary character to be extracted. In sum, this review of the integration of function, structure and evolution of ITS2 will expand the traditional sequence-based ITS2 phylogeny and thus contributes to the tree of life. The generality of ITS2 characteristics may also inspire phylogenetic use of other similar structural regions. Full article

(This article belongs to the Special Issue Advanced Research in Ribosomal RNAs)

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