A close-up view of codon selection in eukaryotic initiation

Lind, Christoffer; Esguerra, Mauricio; Åqvist, Johan

doi:10.1080/15476286.2017.1308998

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…Although at first glance, such issues may not seem important for the interpretation of crystal structures, one could envisage that they may change the outcome of molecular dynamics simulations since the Mg 2+ stabilization effect is much greater than that of K + (Hayatshahi et al 2017). Henceforth, it is highly probable that a decoding site modeled with one or the other ion would behave in significantly different ways and change our perception of the energetics and dynamics of the ribosomal decoding center (Lind et al 2017). Thus, it is recommended to avoid using structures that contain ions with poor stereochemistry for initiating modeling studies (Hashem and Auffinger 2009).…”

Section: The Monovalent Ion Count In Ribosomes Is Underestimatedmentioning

confidence: 99%

Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Leonarski

D’Ascenzo

Auffinger

2018

RNA

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Precise knowledge of Mg 2+ inner-sphere binding site properties is vital for understanding the structure and function of nucleic acid systems. Unfortunately, the PDB, which represents the main source of Mg 2+ binding sites, contains a substantial number of assignment issues that blur our understanding of the functions of these ions. Here, following a previous study devoted to Mg 2+ binding to nucleobase nitrogens, we surveyed nucleic acid X-ray structures from the PDB with resolutions ≤2.9 Å to classify the Mg 2+ inner-sphere binding patterns to nucleotide carbonyl, ribose hydroxyl, cyclic ether, and phosphodiester oxygen atoms. From this classification, we derived a set of "prior-knowledge" nucleobase Mg 2+ binding sites. We report that crystallographic examples of trustworthy nucleobase Mg 2+ binding sites are fewer than expected since many of those are associated with misidentified Na + or K +. We also emphasize that binding of Na + and K + to nucleic acids is much more frequent than anticipated. Overall, we provide evidence derived from X-ray structures that nucleobases are poor inner-sphere binders for Mg 2+ but good binders for monovalent ions. Based on strict stereochemical criteria, we propose an extended set of guidelines designed to help in the assignment and validation of ions directly contacting nucleobase and ribose atoms. These guidelines should help in the interpretation of X-ray and cryo-EM solvent density maps. When borderline Mg 2+ stereochemistry is observed, alternative placement of Na + , K + , or Ca 2+ must be considered. We also critically examine the use of lanthanides (Yb 3+ , Tb 3+) as Mg 2+ substitutes in crystallography experiments.

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Section: The Monovalent Ion Count In Ribosomes Is Underestimatedmentioning

confidence: 99%

Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Leonarski

D’Ascenzo

Auffinger

2018

RNA

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“…Ribosomal scanning of mRNA is generally accepted as the predominant mechanism to locate start codons during the initiation phase of eukaryotic translation [1]. The scanning model posits that, upon cap-dependent attachment to mRNA, ribosomal small subunits (SSUs) move in a 5′ to 3′ direction (at the expense of energy; ‘powered’ motion), while the 5′UTR nucleotide sequence is being probed for codon:anticodon and local ‘nucleotide context’ interactions [1,2,3,4,5,6]. Additionally, several cap-independent [7,8,9], or eIF4E (the main cap-binding protein)-independent mechanisms have been proposed over the years to cater for translation under specific conditions and of special mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Migration of Small Ribosomal Subunits on the 5′ Untranslated Regions of Capped Messenger RNA

Shirokikh

Dutikova

Staroverova

et al. 2019

IJMS

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Several control mechanisms of eukaryotic gene expression target the initiation step of mRNA translation. The canonical translation initiation pathway begins with cap-dependent attachment of the small ribosomal subunit (SSU) to the messenger ribonucleic acid (mRNA) followed by an energy-dependent, sequential ‘scanning’ of the 5′ untranslated regions (UTRs). Scanning through the 5′UTR requires the adenosine triphosphate (ATP)-dependent RNA helicase eukaryotic initiation factor (eIF) 4A and its efficiency contributes to the specific rate of protein synthesis. Thus, understanding the molecular details of the scanning mechanism remains a priority task for the field. Here, we studied the effects of inhibiting ATP-dependent translation and eIF4A in cell-free translation and reconstituted initiation reactions programmed with capped mRNAs featuring different 5′UTRs. An aptamer that blocks eIF4A in an inactive state away from mRNA inhibited translation of capped mRNA with the moderately structured β-globin sequences in the 5′UTR but not that of an mRNA with a poly(A) sequence as the 5′UTR. By contrast, the nonhydrolysable ATP analogue β,γ-imidoadenosine 5′-triphosphate (AMP-PNP) inhibited translation irrespective of the 5′UTR sequence, suggesting that complexes that contain ATP-binding proteins in their ATP-bound form can obstruct and/or actively block progression of ribosome recruitment and/or scanning on mRNA. Further, using primer extension inhibition to locate SSUs on mRNA (‘toeprinting’), we identify an SSU complex which inhibits primer extension approximately eight nucleotides upstream from the usual toeprinting stop generated by SSUs positioned over the start codon. This ‘−8 nt toeprint’ was seen with mRNA 5′UTRs of different length, sequence and structure potential. Importantly, the ‘−8 nt toeprint’ was strongly stimulated by the presence of the cap on the mRNA, as well as the presence of eIFs 4F, 4A/4B and ATP, implying active scanning. We assembled cell-free translation reactions with capped mRNA featuring an extended 5′UTR and used cycloheximide to arrest elongating ribosomes at the start codon. Impeding scanning through the 5′UTR in this system with elevated magnesium and AMP-PNP (similar to the toeprinting conditions), we visualised assemblies consisting of several SSUs together with one full ribosome by electron microscopy, suggesting direct detection of scanning intermediates. Collectively, our data provide additional biochemical, molecular and physical evidence to underpin the scanning model of translation initiation in eukaryotes.

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“…In accordance with these results, a later study by Itoh et al showed that higher serum concentrations of POPs decreased global DNA methylation in a Japanese population [183]. In contrast, a study by Lind et al on a population of 70-year-old Swedish found a relationship between high serum levels of POPs and global DNA hypermethylation [184]. Only one study examined PCB levels in human postmortem brains of patients with neurodevelopmental disorders and found that PCBs 95 was detected in 3/6 Prader-Willi syndrome postmortem brains and 5/6 postmortem brains with Dup15q.…”

Section: Epigenetic Alterations By Environmental Toxicantsmentioning

confidence: 73%

Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism

Tran

Miyake

2017

International Journal of Genomics

116

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The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.

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A close-up view of codon selection in eukaryotic initiation

Cited by 10 publications

References 49 publications

Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Migration of Small Ribosomal Subunits on the 5′ Untranslated Regions of Capped Messenger RNA

Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism

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A close-up view of codon selection in eukaryotic initiation

Cited by 10 publications

References 49 publications

Nucleobase carbonyl groups are poor Mg2+inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Nucleobase carbonyl groups are poor Mg2+inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Migration of Small Ribosomal Subunits on the 5′ Untranslated Regions of Capped Messenger RNA

Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism

Contact Info

Product

Resources

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Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey

Nucleobase carbonyl groups are poor Mg²⁺inner-sphere binders but excellent monovalent ion binders—a critical PDB survey