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Open AccessEditorial

Special Issue: Frontiers in RNA Structure

by Quentin Vicens

Molecules 2020, 25(20), 4843; https://doi.org/10.3390/molecules25204843 - 21 Oct 2020

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Abstract

The frontiers of our knowledge about RNA structure are rapidly moving [...] Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

Research

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16 pages, 2327 KiB

Open AccessArticle

High Affinity Binding of N2-Modified Guanine Derivatives Significantly Disrupts the Ligand Binding Pocket of the Guanine Riboswitch

by Michal M. Matyjasik, Simone D. Hall and Robert T. Batey

Molecules 2020, 25(10), 2295; https://doi.org/10.3390/molecules25102295 - 13 May 2020

Cited by 8 | Viewed by 3629

Abstract

Riboswitches are important model systems for the development of approaches to search for RNA-targeting therapeutics. A principal challenge in finding compounds that target riboswitches is that the effector ligand is typically almost completely encapsulated by the RNA, which severely limits the chemical space [...] Read more.

Riboswitches are important model systems for the development of approaches to search for RNA-targeting therapeutics. A principal challenge in finding compounds that target riboswitches is that the effector ligand is typically almost completely encapsulated by the RNA, which severely limits the chemical space that can be explored. Efforts to find compounds that bind the guanine/adenine class of riboswitches with a high affinity have in part focused on purines modified at the C6 and C2 positions. These studies have revealed compounds that have low to sub-micromolar affinity and, in a few cases, have antimicrobial activity. To further understand how these compounds interact with the guanine riboswitch, we have performed an integrated structural and functional analysis of representative guanine derivatives with modifications at the C8, C6 and C2 positions. Our data indicate that while modifications of guanine at the C6 position are generally unfavorable, modifications at the C8 and C2 positions yield compounds that rival guanine with respect to binding affinity. Surprisingly, C2-modified guanines such as N2-acetylguanine completely disrupt a key Watson–Crick pairing interaction between the ligand and RNA. These compounds, which also modulate transcriptional termination as efficiently as guanine, open up a significant new chemical space of guanine modifications in the search for antimicrobial agents that target purine riboswitches. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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19 pages, 3926 KiB

Open AccessArticle

Good Vibrations: Structural Remodeling of Maturing Yeast Pre-40S Ribosomal Particles Followed by Cryo-Electron Microscopy

by Ramtin Shayan, Dana Rinaldi, Natacha Larburu, Laura Plassart, Stéphanie Balor, David Bouyssié, Simon Lebaron, Julien Marcoux, Pierre-Emmanuel Gleizes and Célia Plisson-Chastang

Molecules 2020, 25(5), 1125; https://doi.org/10.3390/molecules25051125 - 03 Mar 2020

Cited by 13 | Viewed by 4089

Abstract

Assembly of eukaryotic ribosomal subunits is a very complex and sequential process that starts in the nucleolus and finishes in the cytoplasm with the formation of functional ribosomes. Over the past few years, characterization of the many molecular events underlying eukaryotic ribosome biogenesis [...] Read more.

Assembly of eukaryotic ribosomal subunits is a very complex and sequential process that starts in the nucleolus and finishes in the cytoplasm with the formation of functional ribosomes. Over the past few years, characterization of the many molecular events underlying eukaryotic ribosome biogenesis has been drastically improved by the “resolution revolution” of cryo-electron microscopy (cryo-EM). However, if very early maturation events have been well characterized for both yeast ribosomal subunits, little is known regarding the final maturation steps occurring to the small (40S) ribosomal subunit. To try to bridge this gap, we have used proteomics together with cryo-EM and single particle analysis to characterize yeast pre-40S particles containing the ribosome biogenesis factor Tsr1. Our analyses lead us to refine the timing of the early pre-40S particle maturation steps. Furthermore, we suggest that after an early and structurally stable stage, the beak and platform domains of pre-40S particles enter a “vibrating” or “wriggling” stage, that might be involved in the final maturation of 18S rRNA as well as the fitting of late ribosomal proteins into their mature position. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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12 pages, 11099 KiB

Open AccessArticle

Structural Bases for the Fitness Cost of the Antibiotic-Resistance and Lethal Mutations at Position 1408 of 16S rRNA

by Jiro Kondo and Mai Koganei

Molecules 2020, 25(1), 159; https://doi.org/10.3390/molecules25010159 - 31 Dec 2019

Cited by 3 | Viewed by 2886

Abstract

To understand a structural basis for the fitness cost of the A1408G antibiotic-resistance mutation in the ribosomal A-site RNA, we have determined crystal structures of its A1408C and A1408U lethal mutants, and made comparison with previously solved structures of the wild type and [...] Read more.

To understand a structural basis for the fitness cost of the A1408G antibiotic-resistance mutation in the ribosomal A-site RNA, we have determined crystal structures of its A1408C and A1408U lethal mutants, and made comparison with previously solved structures of the wild type and the antibiotic-resistant mutant. The A-site RNA containing an asymmetric internal loop functions as a molecular switch to discriminate a single cognate tRNA from several near-cognate tRNAs by its conformational ON/OFF switching. Overall structures of the “off” states of the A1408C/U lethal mutants are very similar to those of the wild type and the A1408G antibiotic-resistant mutant. However, significant differences are found in local base stacking interactions including the functionally important A1492 and A1493 residues. In the wild type and the A1408G antibiotic-resistant mutant “off” states, both adenines are exposed to the solvent region. On the other hand, one of the corresponding adenines of the lethal A1408C/U mutants stay deeply inside their A-site helices by forming a purine-pyrimidine AoC or A-U base pair and is sandwiched between the upper and lower bases. Therefore, the ON/OFF switching might unfavorably occur in the lethal mutants compared to the wild type and the A1408G antibiotic-resistant mutant. It is probable that bacteria manage to acquire antibiotic resistance without losing the function of the A-site molecular switch by mutating the position 1408 only from A to G, but not to pyrimidine base C or U. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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Review

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17 pages, 2686 KiB

Open AccessReview

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

by Frédéric Poitevin, Artem Kushner, Xinpei Li and Khanh Dao Duc

Molecules 2020, 25(18), 4262; https://doi.org/10.3390/molecules25184262 - 17 Sep 2020

Cited by 18 | Viewed by 4298

Abstract

The extent of ribosomal heterogeneity has caught increasing interest over the past few years, as recent studies have highlighted the presence of structural variations of the ribosome. More precisely, the heterogeneity of the ribosome covers multiple scales, including the dynamical aspects of ribosomal [...] Read more.

The extent of ribosomal heterogeneity has caught increasing interest over the past few years, as recent studies have highlighted the presence of structural variations of the ribosome. More precisely, the heterogeneity of the ribosome covers multiple scales, including the dynamical aspects of ribosomal motion at the single particle level, specialization at the cellular and subcellular scale, or evolutionary differences across species. Upon solving the ribosome atomic structure at medium to high resolution, cryogenic electron microscopy (cryo-EM) has enabled investigating all these forms of heterogeneity. In this review, we present some recent advances in quantifying ribosome heterogeneity, with a focus on the conformational and evolutionary variations of the ribosome and their functional implications. These efforts highlight the need for new computational methods and comparative tools, to comprehensively model the continuous conformational transition pathways of the ribosome, as well as its evolution. While developing these methods presents some important challenges, it also provides an opportunity to extend our interpretation and usage of cryo-EM data, which would more generally benefit the study of molecular dynamics and evolution of proteins and other complexes. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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19 pages, 2912 KiB

Open AccessReview

RNA Granules: A View from the RNA Perspective

by Siran Tian, Harrison A. Curnutte and Tatjana Trcek

Molecules 2020, 25(14), 3130; https://doi.org/10.3390/molecules25143130 - 08 Jul 2020

Cited by 42 | Viewed by 8261

Abstract

RNA granules are ubiquitous. Composed of RNA-binding proteins and RNAs, they provide functional compartmentalization within cells. They are inextricably linked with RNA biology and as such are often referred to as the hubs for post-transcriptional regulation. Much of the attention has been given [...] Read more.

RNA granules are ubiquitous. Composed of RNA-binding proteins and RNAs, they provide functional compartmentalization within cells. They are inextricably linked with RNA biology and as such are often referred to as the hubs for post-transcriptional regulation. Much of the attention has been given to the proteins that form these condensates and thus many fundamental questions about the biology of RNA granules remain poorly understood: How and which RNAs enrich in RNA granules, how are transcripts regulated in them, and how do granule-enriched mRNAs shape the biology of a cell? In this review, we discuss the imaging, genetic, and biochemical data, which have revealed that some aspects of the RNA biology within granules are carried out by the RNA itself rather than the granule proteins. Interestingly, the RNA structure has emerged as an important feature in the post-transcriptional control of granule transcripts. This review is part of the Special Issue in the Frontiers in RNA structure in the journal Molecules. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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28 pages, 4500 KiB

Open AccessReview

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

by Charles Bou-Nader and Jinwei Zhang

Molecules 2020, 25(12), 2881; https://doi.org/10.3390/molecules25122881 - 23 Jun 2020

Cited by 22 | Viewed by 4549

Abstract

In comparison with the pervasive use of protein dimers and multimers in all domains of life, functional RNA oligomers have so far rarely been observed in nature. Their diminished occurrence contrasts starkly with the robust intrinsic potential of RNA to multimerize through long-range [...] Read more.

In comparison with the pervasive use of protein dimers and multimers in all domains of life, functional RNA oligomers have so far rarely been observed in nature. Their diminished occurrence contrasts starkly with the robust intrinsic potential of RNA to multimerize through long-range base-pairing (“kissing”) interactions, self-annealing of palindromic or complementary sequences, and stable tertiary contact motifs, such as the GNRA tetraloop-receptors. To explore the general mechanics of RNA dimerization, we performed a meta-analysis of a collection of exemplary RNA homodimer structures consisting of viral genomic elements, ribozymes, riboswitches, etc., encompassing both functional and fortuitous dimers. Globally, we found that domain-swapped dimers and antiparallel, head-to-tail arrangements are predominant architectural themes. Locally, we observed that the same structural motifs, interfaces and forces that enable tertiary RNA folding also drive their higher-order assemblies. These feature prominently long-range kissing loops, pseudoknots, reciprocal base intercalations and A-minor interactions. We postulate that the scarcity of functional RNA multimers and limited diversity in multimerization motifs may reflect evolutionary constraints imposed by host antiviral immune surveillance and stress sensing. A deepening mechanistic understanding of RNA multimerization is expected to facilitate investigations into RNA and RNP assemblies, condensates, and granules and enable their potential therapeutical targeting. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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13 pages, 1984 KiB

Open AccessReview

Yeast Telomerase RNA Flexibly Scaffolds Protein Subunits: Results and Repercussions

by David C. Zappulla

Molecules 2020, 25(12), 2750; https://doi.org/10.3390/molecules25122750 - 14 Jun 2020

Cited by 7 | Viewed by 3666

Abstract

It is said that “hindsight is 20-20,” so, given the current year, it is an opportune time to review and learn from experiences studying long noncoding RNAs. Investigation of the Saccharomyces cerevisiae telomerase RNA, TLC1, has unveiled striking flexibility in terms of both [...] Read more.

It is said that “hindsight is 20-20,” so, given the current year, it is an opportune time to review and learn from experiences studying long noncoding RNAs. Investigation of the Saccharomyces cerevisiae telomerase RNA, TLC1, has unveiled striking flexibility in terms of both structural and functional features. Results support the “flexible scaffold” hypothesis for this 1157-nt telomerase RNA. This model describes TLC1 acting as a tether for holoenzyme protein subunits, and it also may apply to a plethora of RNAs beyond telomerase, such as types of lncRNAs. In this short perspective review, I summarize findings from studying the large yeast telomerase ribonucleoprotein (RNP) complex in the hope that this hindsight will sharpen foresight as so many of us seek to mechanistically understand noncoding RNA molecules from vast transcriptomes. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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19 pages, 4150 KiB

Open AccessReview

Cooperative Analysis of Structural Dynamics in RNA-Protein Complexes by Single-Molecule Förster Resonance Energy Transfer Spectroscopy

by Nathalie Meiser, Christin Fuks and Martin Hengesbach

Molecules 2020, 25(9), 2057; https://doi.org/10.3390/molecules25092057 - 28 Apr 2020

Cited by 4 | Viewed by 2978

Abstract

RNA-protein complexes (RNPs) are essential components in a variety of cellular processes, and oftentimes exhibit complex structures and show mechanisms that are highly dynamic in conformation and structure. However, biochemical and structural biology approaches are mostly not able to fully elucidate the structurally [...] Read more.

RNA-protein complexes (RNPs) are essential components in a variety of cellular processes, and oftentimes exhibit complex structures and show mechanisms that are highly dynamic in conformation and structure. However, biochemical and structural biology approaches are mostly not able to fully elucidate the structurally and especially conformationally dynamic and heterogeneous nature of these RNPs, to which end single molecule Förster resonance energy transfer (smFRET) spectroscopy can be harnessed to fill this gap. Here we summarize the advantages of strategic smFRET studies to investigate RNP dynamics, complemented by structural and biochemical data. Focusing on recent smFRET studies of three essential biological systems, we demonstrate that investigation of RNPs on a single molecule level can answer important functional questions that remained elusive with structural or biochemical approaches alone: The complex structural rearrangements throughout the splicing cycle, unwinding dynamics of the G-quadruplex (G4) helicase RHAU, and aspects in telomere maintenance regulation and synthesis. Full article

(This article belongs to the Special Issue Frontiers in RNA Structure)

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