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Biochemical Society Transactions Aug 2018The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome - the cellular machine that mediates... (Review)
Review
The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome - the cellular machine that mediates protein synthesis - is typically seen as a key, but invariant, player in this process. This is because translational control is thought to be mediated by other auxiliary factors while ribosome recruitment is seen as the end-point of regulation. However, recent developments have made it clear that heterogeneous ribosome types can exist in different tissues, and more importantly, that these ribosomes can preferentially translate different subsets of mRNAs. In so doing, heterogeneous ribosomes could be key regulatory players in differentiation and development. Here, we examine current evidence for the existence of different ribosome types and how they might arise. In particular, we will take a close look at the mechanisms through which these ribosomes might mediate selective mRNA translation. We also summarize recently developed techniques/approaches that will aid in our understanding of the functions of such specialized ribosomes.
Topics: Humans; Protein Biosynthesis; Proteins; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 29986937
DOI: 10.1042/BST20160426 -
Current Opinion in Chemical Biology Oct 2019Synthetic biology aims to rewire cellular activities and functionality by implementing genetic circuits with high biocomputing capabilities. Recent efforts led to the... (Review)
Review
Synthetic biology aims to rewire cellular activities and functionality by implementing genetic circuits with high biocomputing capabilities. Recent efforts led to the development of smart sensing interfaces which integrate multiple inputs to activate desired outputs in a highly specific and sensitive manner. In this review, we highlight protein-based interfaces that sense intracellular or extracellular cues providing information about dynamic environmental changes and cellular state. We will also discuss different mechanisms of regulation of gene expression connected to the sensors to develop diagnostic and therapeutic devices. We conclude discussing challenges and opportunities for biomedical applications of synthetic mammalian protein-based devices.
Topics: Animals; Gene Expression Regulation; Gene Regulatory Networks; Mammals; Protein Biosynthesis; Protein Processing, Post-Translational; Proteins; Signal Transduction; Synthetic Biology; Transcription, Genetic
PubMed: 31158655
DOI: 10.1016/j.cbpa.2019.04.014 -
Current Protocols in Protein Science Nov 2014Pulse-chase analysis is a well-established and highly adaptable tool for studying the life cycle of endogenous proteins, including their synthesis, folding, subunit... (Review)
Review
Pulse-chase analysis is a well-established and highly adaptable tool for studying the life cycle of endogenous proteins, including their synthesis, folding, subunit assembly, intracellular transport, post-translational processing, and degradation. This unit describes the performance and analysis of a radiolabel pulse-chase experiment for following the folding and cell surface trafficking of a trimeric murine MHC class I glycoprotein. In particular, the unit focuses on the precise timing of pulse-chase experiments to evaluate early/short-time events in protein maturation in both suspended and strictly adherent cell lines. The advantages and limitations of radiolabel pulse-chase experiments are discussed, and a comprehensive section for troubleshooting is provided. Further, ways to quantitatively represent pulse-chase results are described, and feasible interpretations on protein maturation are suggested. The protocols can be adapted to investigate a variety of proteins that may mature in very different ways.
Topics: Animals; Histocompatibility Antigens Class I; Isotope Labeling; Mice; Protein Biosynthesis; Protein Folding
PubMed: 25367008
DOI: 10.1002/0471140864.ps3003s78 -
Cell Systems Feb 2020How do cells maintain relative proportions of protein complex components? Advances in quantitative, genome-wide measurements have begun to shed light onto the roles of... (Review)
Review
How do cells maintain relative proportions of protein complex components? Advances in quantitative, genome-wide measurements have begun to shed light onto the roles of protein synthesis and degradation in establishing the precise proportions in living cells: on the one hand, ribosome profiling studies indicate that proteins are already produced in the correct relative proportions. On the other hand, proteomic studies found that many complexes contain subunits that are made in excess and subsequently degraded. Here, we discuss these seemingly contradictory findings, emerging principles, and remaining open questions. We conclude that establishing precise protein levels involves both coordinated synthesis and post-translational fine-tuning via protein degradation.
Topics: Protein Biosynthesis; Proteins
PubMed: 32105631
DOI: 10.1016/j.cels.2020.01.004 -
Cold Spring Harbor Perspectives in... Jun 2019The many steps of gene expression, from the transcription of a gene to the production of its protein product, are well understood. Yet, transcriptional regulation has... (Review)
Review
The many steps of gene expression, from the transcription of a gene to the production of its protein product, are well understood. Yet, transcriptional regulation has been the focal point for the study of gene expression during development. However, quantitative studies reveal that messenger RNA (mRNA) levels are not necessarily good predictors of the respective proteins' levels in a cell. This discrepancy is, at least in part, the result of developmentally regulated, translational mechanisms that control the spatiotemporal regulation of gene expression. In this review, we focus on translational regulatory mechanisms mediating global transitions in gene expression: the shift from the maternal to the embryonic developmental program in the early embryo and the switch from the self-renewal of stem cells to differentiation in the adult.
Topics: Animals; Cell Differentiation; Embryonic Stem Cells; Gene Expression Regulation, Developmental; Protein Biosynthesis; Protein Processing, Post-Translational; RNA, Messenger
PubMed: 30082467
DOI: 10.1101/cshperspect.a032987 -
Journal of Applied Physiology... Nov 2015
Topics: Animals; Congresses as Topic; Humans; Hypoxia; Protein Biosynthesis; Translational Research, Biomedical
PubMed: 26338459
DOI: 10.1152/japplphysiol.00745.2015 -
Wiley Interdisciplinary Reviews. RNA Jan 2017Quality control processes are widespread and play essential roles in detecting defective molecules and removing them in order to maintain organismal fitness. Aberrant... (Review)
Review
Quality control processes are widespread and play essential roles in detecting defective molecules and removing them in order to maintain organismal fitness. Aberrant messenger RNA (mRNA) molecules, unless properly managed, pose a significant hurdle to cellular proteostasis. Often mRNAs harbor premature stop codons, possess structures that present a block to the translational machinery, or lack stop codons entirely. In eukaryotes, the three cytoplasmic mRNA-surveillance processes, nonsense-mediated decay (NMD), no-go decay (NGD), and nonstop decay (NSD), evolved to cope with these aberrant mRNAs, respectively. Nonstop mRNAs and mRNAs that inhibit translation elongation are especially problematic as they sequester valuable ribosomes from the translating ribosome pool. As a result, in addition to RNA degradation, NSD and NGD are intimately coupled to ribosome rescue in all domains of life. Furthermore, protein products produced from all three classes of defective mRNAs are more likely to malfunction. It is not surprising then that these truncated nascent protein products are subject to degradation. Over the past few years, many studies have begun to document a central role for the ribosome in initiating the RNA and protein quality control processes. The ribosome appears to be responsible for recognizing the target mRNAs as well as for recruiting the factors required to carry out the processes of ribosome rescue and nascent protein decay. WIREs RNA 2017, 8:e1366. doi: 10.1002/wrna.1366 For further resources related to this article, please visit the WIREs website.
Topics: Animals; Humans; Peptide Chain Elongation, Translational; Peptide Chain Termination, Translational; Protein Biosynthesis; RNA, Messenger; Ribosomes
PubMed: 27193249
DOI: 10.1002/wrna.1366 -
Biochimie Jul 2015Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on... (Review)
Review
Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation.
Topics: Animals; Humans; Protein Biosynthesis; Protein Folding; Ribosomes; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 25701549
DOI: 10.1016/j.biochi.2015.02.006 -
Methods (San Diego, Calif.) Sep 2019Protein synthesis is critical to cell survival and translation regulation is essential to post-transcriptional gene expression regulation. Disorders of this process,... (Review)
Review
Protein synthesis is critical to cell survival and translation regulation is essential to post-transcriptional gene expression regulation. Disorders of this process, particularly through RNA-binding proteins, is associated with the development and progression of a number of diseases, including cancers. However, the molecular mechanisms underlying the initiation of protein synthesis are intricate, making it difficult to find a drug that interferes with this process. Chemical probes are useful in elucidating the structures of RNA-protein complex and molecular mechanism of biological events. Moreover, some of these chemical probes show certain therapeutic benefits and can be further developed as leading compounds. Here, we will briefly review the general process and mechanism of protein synthesis, and emphasis on chemical probes in examples of probing the RNA structural changes and RNA-protein interactions. Moreover, the therapeutic potential of these probes is also discussed to give a comprehensive understanding.
Topics: Gene Expression Regulation; Humans; Molecular Biology; Nucleic Acid Conformation; Protein Biosynthesis; RNA; RNA-Binding Proteins; Small Molecule Libraries
PubMed: 31185274
DOI: 10.1016/j.ymeth.2019.06.004 -
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