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Neuropharmacology Jan 2014Brain-derived neurotrophic factor (BDNF) is a critical activity-dependent modulator of gene expression, which can regulate both transcription and translation. Several... (Review)
Review
Brain-derived neurotrophic factor (BDNF) is a critical activity-dependent modulator of gene expression, which can regulate both transcription and translation. Several functions of BDNF, including the induction of dendrite outgrowth and long-term synaptic plasticity, are known to depend, in particular, upon the ability of BDNF to regulate protein synthesis. Although BDNF modestly increases total neuronal protein synthesis, substantial evidence indicates that BDNF induces the translation of only a small subset of expressed mRNAs and demonstrates an extraordinary degree of transcript specificity. The mechanism by which BDNF selectively upregulates the translation of only a discrete group of mRNAs is of intrinsic importance to its trophic function in promoting neuronal growth and plasticity, and is the focus of this review. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.
Topics: Animals; Brain-Derived Neurotrophic Factor; Humans; MicroRNAs; Neurons; Protein Biosynthesis; RNA, Messenger
PubMed: 23707639
DOI: 10.1016/j.neuropharm.2013.05.004 -
Cold Spring Harbor Perspectives in... Sep 2012Decades of extensive biochemical and biophysical research have outlined the mechanism of translation. Rich structural studies have provided detailed snapshots of the... (Review)
Review
Decades of extensive biochemical and biophysical research have outlined the mechanism of translation. Rich structural studies have provided detailed snapshots of the translational machinery at all phases of the translation cycle. However, the relationship between structural dynamics, composition, and function remains unknown. The multistep nature of each stage of the translation cycle results in rapid desynchronization of individual ribosomes, thus hindering elucidation of the underlying mechanisms by conventional bulk biophysical and biochemical methods. Single-molecule approaches unsusceptible to these complications have led to the first glances at both compositional and conformational dynamics on the ribosome and their impact on translational control. These experiments provide the necessary link between static structure and mechanism, often providing new perspectives. Here we review recent advances in the field and their relationship to structural and biochemical data.
Topics: Models, Genetic; Molecular Biology; Molecular Conformation; Peptide Chain Elongation, Translational; Prokaryotic Initiation Factor-2; Protein Biosynthesis; RNA, Transfer; Ribosomes
PubMed: 22798542
DOI: 10.1101/cshperspect.a011551 -
Cell Reports Jan 2016The economy of protein production is central to cell physiology, being intimately linked with cell division rate and cell size. Attempts to model cellular physiology are...
The economy of protein production is central to cell physiology, being intimately linked with cell division rate and cell size. Attempts to model cellular physiology are limited by the scarcity of experimental data defining the molecular processes limiting protein expression. Here, we distinguish the relative contribution of gene transcription and protein translation to the slower proliferation of budding yeast producing excess levels of unneeded proteins. In contrast to widely held assumptions, rapidly growing cells are not universally limited by ribosome content. Rather, transcription dominates cost under some conditions (e.g., low phosphate), translation in others (e.g., low nitrogen), and both in other conditions (e.g., rich media). Furthermore, cells adapted to enforced protein production by becoming larger and increasing their endogenous protein levels, suggesting limited competition for common resources. We propose that rapidly growing cells do not exhaust their resources to maximize growth but maintain sufficient reserves to accommodate changing requirements.
Topics: Gene Expression Regulation, Fungal; Protein Biosynthesis; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription, Genetic
PubMed: 26725116
DOI: 10.1016/j.celrep.2015.12.015 -
Philosophical Transactions of the Royal... Mar 2017The basic steps of protein synthesis are carried out by the ribosome, a very large and complex ribonucleoprotein particle. In keeping with its proposed emergence from an... (Review)
Review
The basic steps of protein synthesis are carried out by the ribosome, a very large and complex ribonucleoprotein particle. In keeping with its proposed emergence from an RNA world, all three of its core mechanisms-aminoacyl-tRNA selection, catalysis of peptide bond formation and coupled translocation of mRNA and tRNA-are embodied in the properties of ribosomal RNA, while its proteins play a supportive role.This article is part of the themed issue 'Perspectives on the ribosome'.
Topics: Origin of Life; Protein Biosynthesis; RNA; Transfer RNA Aminoacylation; Translocation, Genetic
PubMed: 28138073
DOI: 10.1098/rstb.2016.0187 -
Cold Spring Harbor Perspectives in... Aug 2018In this review, we highlight the current understanding of translation elongation and recoding in eukaryotes. In addition to providing an overview of the process, recent... (Review)
Review
In this review, we highlight the current understanding of translation elongation and recoding in eukaryotes. In addition to providing an overview of the process, recent advances in our understanding of the role of the factor eIF5A in both translation elongation and termination are discussed. We also highlight mechanisms of translation recoding with a focus on ribosomal frameshifting during elongation. We see that the balance between the basic steps in elongation and the less common recoding events is determined by the kinetics of the different processes as well as by specific sequence determinants.
Topics: Eukaryota; Frameshifting, Ribosomal; Gene Expression Regulation; Protein Biosynthesis
PubMed: 29610120
DOI: 10.1101/cshperspect.a032649 -
Open Biology Jul 2019Many antibiotics available in the clinic today directly inhibit bacterial translation. Despite the past success of such drugs, their efficacy is diminishing with the... (Review)
Review
Many antibiotics available in the clinic today directly inhibit bacterial translation. Despite the past success of such drugs, their efficacy is diminishing with the spread of antibiotic resistance. Through the use of ribosomal modifications, ribosomal protection proteins, translation elongation factors and mistranslation, many pathogens are able to establish resistance to common therapeutics. However, current efforts in drug discovery are focused on overcoming these obstacles through the modification or discovery of new treatment options. Here, we provide an overview for common mechanisms of resistance to translation-targeting drugs and summarize several important breakthroughs in recent drug development.
Topics: Animals; Anti-Bacterial Agents; Drug Discovery; Drug Resistance, Bacterial; Humans; Molecular Targeted Therapy; Protein Biosynthesis; Protein Processing, Post-Translational; Ribosomal Proteins; Ribosomes
PubMed: 31288624
DOI: 10.1098/rsob.190051 -
PloS One 2020In the past two decades, research into the biochemical, biophysical and structural properties of the ribosome have revealed many different steps of protein translation....
In the past two decades, research into the biochemical, biophysical and structural properties of the ribosome have revealed many different steps of protein translation. Nevertheless, a complete understanding of how they lead to a rapid and accurate protein synthesis still remains a challenge. Here we consider a coarse network analysis in the bacterial ribosome formed by the connectivity between ribosomal (r) proteins and RNAs at different stages in the elongation cycle. The ribosomal networks are found to be dis-assortative and small world, implying that the structure allows for an efficient exchange of information between distant locations. An analysis of centrality shows that the second and fifth domains of 23S rRNA are the most important elements in all of the networks. Ribosomal protein hubs connect to much fewer nodes but are shown to provide important connectivity within the network (high closeness centrality). A modularity analysis reveals some of the different functional communities, indicating some known and some new possible communication pathways Our mathematical results confirm important communication pathways that have been discussed in previous research, thus verifying the use of this technique for representing the ribosome, and also reveal new insights into the collective function of ribosomal elements.
Topics: Bacteria; Computational Biology; Gene Regulatory Networks; Protein Biosynthesis; RNA, Ribosomal, 23S; Ribosomal Proteins; Ribosomes; Transcription Elongation, Genetic
PubMed: 33017414
DOI: 10.1371/journal.pone.0239700 -
Neurochemical Research Jun 2014Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. Most FXS cases occur due to the expansion of the CGG trinucleotide... (Review)
Review
Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. Most FXS cases occur due to the expansion of the CGG trinucleotide repeats in the 5' un-translated region of FMR1, which leads to hypermethylation and in turn silences the expression of FMRP (fragile X mental retardation protein). Numerous studies have demonstrated that FMRP interacts with both coding and non-coding RNAs and represses protein synthesis at dendritic and synaptic locations. In the absence of FMRP, the basal protein translation is enhanced and not responsive to neuronal stimulation. The altered protein translation may contribute to functional abnormalities in certain aspects of synaptic plasticity and intracellular signaling triggered by Gq-coupled receptors. This review focuses on the current understanding of FMRP function and potential therapeutic strategies that are mainly based on the manipulation of FMRP targets and knowledge gained from FXS pathophysiology.
Topics: Animals; Drug Delivery Systems; Fragile X Mental Retardation Protein; Fragile X Syndrome; Humans; Minocycline; Protein Biosynthesis
PubMed: 24346713
DOI: 10.1007/s11064-013-1229-3 -
Biochimica Et Biophysica Acta.... Sep 2021Genetic mutations that cause hereditary diseases usually affect the composition of the transcribed mRNA and its encoded protein, leading to instability of the mRNA... (Review)
Review
Genetic mutations that cause hereditary diseases usually affect the composition of the transcribed mRNA and its encoded protein, leading to instability of the mRNA and/or the protein. Sometimes, however, such mutations affect the synthesis, the processing or the translation of the mRNA, with similar disastrous effects. We here present an overview of mRNA synthesis, its posttranscriptional modification and its translation into protein. We then indicate which elements in these processes are known to be affected by pathogenic mutations, but we restrict our review to mutations in cis, in the DNA of the gene that encodes the affected protein. These mutations can be in enhancer or promoter regions of the gene, which act as binding sites for transcription factors involved in pre-mRNA synthesis. We also describe mutations in polyadenylation sequences and in splice site regions, exonic and intronic, involved in intron removal. Finally, we include mutations in the Kozak sequence in mRNA, which is involved in protein synthesis. We provide examples of genetic diseases caused by mutations in these DNA regions and refer to databases to help identify these regions. The over-all knowledge of mRNA synthesis, processing and translation is essential for improvement of the diagnosis of patients with genetic diseases.
Topics: Animals; Humans; Mutation; Protein Biosynthesis; Protein Processing, Post-Translational; RNA, Messenger
PubMed: 33971252
DOI: 10.1016/j.bbadis.2021.166166 -
Cell Systems Sep 2017Protein turnover maintains the recycling needs of the proteome, and its malfunction has been linked to aging and age-related diseases. However, not all proteins...
Protein turnover maintains the recycling needs of the proteome, and its malfunction has been linked to aging and age-related diseases. However, not all proteins turnover equally, and the factors that contribute to accelerate or slow down turnover are mostly unknown. We measured turnover rates for 3,160 proteins in exponentially growing yeast and analyzed their dependence on physical, functional, and genetic properties. We found that functional characteristics, including protein localization, complex membership, and connectivity, have greater effect on turnover than sequence elements. We also found that protein turnover and mRNA turnover are correlated. Analysis under nutrient perturbation and osmotic stress revealed that protein turnover highly depends on cellular state and is faster when proteins are being actively used. Finally, stress-induced changes in protein and transcript abundance correlated with changes in protein turnover. This study provides a resource of protein turnover rates and principles to understand the recycling needs of the proteome under basal conditions and perturbation.
Topics: Half-Life; Osmotic Pressure; Protein Biosynthesis; Protein Stability; Proteins; Proteolysis; Proteome; Proteomics; RNA Stability; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 28918244
DOI: 10.1016/j.cels.2017.08.008