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Structural basis for stop codon recognition in eukaryotes
All eukaryotes utilize a single termination factor, eRF1, to halt translation when the ribosome encounters one of three possible stop codons; here electron cryo-microscopy structures of ribosome–eRF1 complexes in the process of recognizing each stop codon reveal how stop codons are discriminated from sense codons.
How mRNA knows when to stop
Mammalian messenger RNAs utilize three stop codons, but have a single termination factor, eRF1, that can recognize all three. To understand how eRF1 can distinguish stop codons from sense codons, Alan Brown
et al
. determined the structures of the mammalian 80S ribosome bound to eRF1 and mRNAs containing each of the stop codons. They find that two nucleotides from the 18S rRNA are stacked with two of the stop codon nucleotides, and the next nucleotide, to compact the mRNA, a conformation that favours stop codons to the exclusion of sense codons.
Termination of protein synthesis occurs when a translating ribosome encounters one of three universally conserved stop codons: UAA, UAG or UGA. Release factors recognize stop codons in the ribosomal A-site to mediate release of the nascent chain and recycling of the ribosome. Bacteria decode stop codons using two separate release factors with differing specificities for the second and third bases
1
. By contrast, eukaryotes rely on an evolutionarily unrelated omnipotent release factor (eRF1) to recognize all three stop codons
2
. The molecular basis of eRF1 discrimination for stop codons over sense codons is not known. Here we present cryo-electron microscopy (cryo-EM) structures at 3.5–3.8 Å resolution of mammalian ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site. Binding of eRF1 flips nucleotide A1825 of 18S ribosomal RNA so that it stacks on the second and third stop codon bases. This configuration pulls the fourth position base into the A-site, where it is stabilized by stacking against G626 of 18S rRNA. Thus, eRF1 exploits two rRNA nucleotides also used during transfer RNA selection to drive messenger RNA compaction. In this compacted mRNA conformation, stop codons are favoured by a hydrogen-bonding network formed between rRNA and essential eRF1 residues that constrains the identity of the bases. These results provide a molecular framework for eukaryotic stop codon recognition and have implications for future studies on the mechanisms of canonical and premature translation termination
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Journal Article
Greek colonization in local contexts : case studies in colonial interactions
Greek Colonization in Local Context' takes a fresh look at Greek colonies around Europe and Black Sea. The emphasis is on cultural interaction, transformation and the repercussions and local reactions to colonization in social, religious and cultural terms. Papers examine the archaeological evidence for cultural interaction in a series of case studies from locations around the Mediterranean and Black Sea regions, at a variety of scales. Contributors consider the effects of colonization on urban life and developments in cities and smaller settlements as well as in the rural landscapes surrounding and supporting them. This collection of new papers by leading scholars reveals fascinating details of the native response to the imposition of Greek rule and the indigenous input into early state development in the Mediterranean and adjacent regions.
Book
A General Business Model for Marine Reserves
Marine reserves are an effective tool for protecting biodiversity locally, with potential economic benefits including enhancement of local fisheries, increased tourism, and maintenance of ecosystem services. However, fishing communities often fear short-term income losses associated with closures, and thus may oppose marine reserves. Here we review empirical data and develop bioeconomic models to show that the value of marine reserves (enhanced adjacent fishing + tourism) may often exceed the pre-reserve value, and that economic benefits can offset the costs in as little as five years. These results suggest the need for a new business model for creating and managing reserves, which could pay for themselves and turn a profit for stakeholder groups. Our model could be expanded to include ecosystem services and other benefits, and it provides a general framework to estimate costs and benefits of reserves and to develop such business models.
Journal Article
Structures of translationally inactive mammalian ribosomes
The cellular levels and activities of ribosomes directly regulate gene expression during numerous physiological processes. The mechanisms that globally repress translation are incompletely understood. Here, we use electron cryomicroscopy to analyze inactive ribosomes isolated from mammalian reticulocytes, the penultimate stage of red blood cell differentiation. We identify two types of ribosomes that are translationally repressed by protein interactions. The first comprises ribosomes sequestered with elongation factor 2 (eEF2) by SERPINE mRNA binding protein 1 (SERBP1) occupying the ribosomal mRNA entrance channel. The second type are translationally repressed by a novel ribosome-binding protein, interferon-related developmental regulator 2 (IFRD2), which spans the P and E sites and inserts a C-terminal helix into the mRNA exit channel to preclude translation. IFRD2 binds ribosomes with a tRNA occupying a noncanonical binding site, the ‘Z site’, on the ribosome. These structures provide functional insights into how ribosomal interactions may suppress translation to regulate gene expression.
Journal Article
Mangroves in the Gulf of California increase fishery yields
Mangroves are disappearing rapidly worldwide despite their well documented biodiversity and the ecosystem services they provide. Failure to link ecological processes and their societal benefits has favored highly destructive aquaculture and tourism developments that threaten mangroves and result in costly \"externalities.\" Specifically, the potentially irreparable damage to fisheries because of mangrove loss has been belittled and is greatly underestimated. Here, we show that, in the Gulf of California, fisheries landings are positively related to the local abundance of mangroves and, in particular, to the productive area in the mangrove-water fringe that is used as nursery and/or feeding grounds by many commercial species. Mangrove-related fish and crab species account for 32% of the small-scale fisheries landings in the region. The annual economic median value of these fisheries is US $37,500 per hectare of mangrove fringe, falling within the higher end of values previously calculated worldwide for all mangrove services together. The ten-year discounted value of one hectare of fringe is >300 times the official cost set by the Mexican government. The destruction of mangroves has a strong economic impact on local fishing communities and on food production in the region. Our valuation of the services provided by mangroves may prove useful in making appropriate decisions for a more efficient and sustainable use of wetlands.
Journal Article
Prednisolone Attenuates Improvement of Cardiac and Skeletal Contractile Function and Histopathology by Lisinopril and Spironolactone in the mdx Mouse Model of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology.
Journal Article
Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin
The naturally occurring nucleotide 2-deoxy-adenosine 5′-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin–myosin interactions that underpin sarcomere dynamics. Exploiting dATP as a molecular probe, we assess how small changes in myosin structure translate to electrostatic-based changes in sarcomere function to augment contractility in cardiac muscle. Through Brownian dynamics simulation and computational structural analysis, we found that deoxy-hydrolysis products [2-deoxy-adenosine 5′-diphosphate (dADP) and inorganic phosphate (Pi)] bound to prepowerstroke myosin induce an allosteric restructuring of the actin-binding surface on myosin to increase the rate of cross-bridge formation. We then show experimentally that this predicted effect translates into increased electrostatic interactions between actin and cardiac myosin in vitro. Finally, using small-angle X-ray diffraction analysis of sarcomere structure, we demonstrate that the proposed increased electrostatic affinity of myosin for actin causes a disruption of the resting conformation of myosin motors, resulting in their repositioning toward the thin filament before activation. The dATP-mediated structural alterations in myosin reported here may provide insight into an improved criterion for the design or selection of small molecules to be developed as therapeutic agents to treat systolic dysfunction.
Journal Article
Understanding the Challenges, Yet Focusing on the Successes : An Investigation into Indigenous University Students' Academic Success
This paper reports on experiences of Indigenous students and staff involved in Bond Indigenous Tutoring (BIT). It aimed to gain insight regarding topics including challenges faced by Indigenous students, why some students discontinued their studies, and concepts of success at university. Findings revealed the main challenges including the transition from secondary to tertiary education and not being prepared academically. BIT staff identified family responsibilities and being dislocated from kinship networks as challenges, while students stated these were factors explaining why Indigenous students discontinued their studies. A whole of university approach was found to be required to effectively support Indigenous students. Success was defined as more than Grade Point Average, as it entailed being able to enjoy future endeavours. This paper contributes to the evidence that tuition programmes and Indigenous centres at university are key contributors to success, and it is argued that such success must become the norm as opposed to the exception. [Author abstract]
Journal Article
Structural characterization of ribosome recruitment and translocation by type IV IRES
Viral mRNA sequences with a type IV IRES are able to initiate translation without any host initiation factors. Initial recruitment of the small ribosomal subunit as well as two translocation steps before the first peptidyl transfer are essential for the initiation of translation by these mRNAs. Using electron cryomicroscopy (cryo-EM) we have structurally characterized at high resolution how the Cricket Paralysis Virus Internal Ribosomal Entry Site (CrPV-IRES) binds the small ribosomal subunit (40S) and the translocation intermediate stabilized by elongation factor 2 (eEF2). The CrPV-IRES restricts the otherwise flexible 40S head to a conformation compatible with binding the large ribosomal subunit (60S). Once the 60S is recruited, the binary CrPV-IRES/80S complex oscillates between canonical and rotated states (Fernández et al., 2014 ; Koh et al., 2014 ), as seen for pre-translocation complexes with tRNAs. Elongation factor eEF2 with a GTP analog stabilizes the ribosome-IRES complex in a rotated state with an extra ~3 degrees of rotation. Key residues in domain IV of eEF2 interact with pseudoknot I (PKI) of the CrPV-IRES stabilizing it in a conformation reminiscent of a hybrid tRNA state. The structure explains how diphthamide, a eukaryotic and archaeal specific post-translational modification of a histidine residue of eEF2, is involved in translocation.
Journal Article