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Antimicrobial Agents and Chemotherapy Apr 2017Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are... (Review)
Review
Antimicrobial peptides (AMPs) are expressed in various living organisms as first-line host defenses against potential harmful encounters in their surroundings. AMPs are short polycationic peptides exhibiting various antimicrobial activities. The principal antibacterial activity is attributed to the membrane-lytic mechanism which directly interferes with the integrity of the bacterial cell membrane and cell wall. In addition, a number of AMPs form a transmembrane channel in the membrane by self-aggregation or polymerization, leading to cytoplasm leakage and cell death. However, an increasing body of evidence has demonstrated that AMPs are able to exert intracellular inhibitory activities as the primary or supportive mechanisms to achieve efficient killing. In this review, we focus on the major intracellular targeting activities reported in AMPs, which include nucleic acids and protein biosynthesis and protein-folding, protease, cell division, cell wall biosynthesis, and lipopolysaccharide inhibition. These multifunctional AMPs could serve as the potential lead peptides for the future development of novel antibacterial agents with improved therapeutic profiles.
Topics: Anti-Infective Agents; Antimicrobial Cationic Peptides; Cell Membrane; Cell Wall; Microbial Sensitivity Tests; Protein Biosynthesis; Protein Folding
PubMed: 28167546
DOI: 10.1128/AAC.02340-16 -
Cold Spring Harbor Perspectives in... Jun 2018The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time... (Review)
Review
The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic translation. Currently, there is much interest in targeting eukaryotic translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the eukaryotic translation initiation apparatus and provide an update on their potential application to the treatment of disease.
Topics: Animals; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Protein Biosynthesis
PubMed: 29440069
DOI: 10.1101/cshperspect.a032995 -
The Journal of Biological Chemistry Jul 2020Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental... (Review)
Review
Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental conditions is control of gene expression at the level of protein synthesis. At each of the three major steps of translation-initiation, elongation, and termination-cells use stimuli to tune translation rate and cellular protein concentrations. For example, changes in nutrient concentrations in the cell can lead to translational responses involving mechanisms such as dynamic folding of riboswitches during translation initiation or the synthesis of alarmones, which drastically alter cell physiology. Moreover, the cell can fine-tune the levels of specific protein products using programmed ribosome pausing or inducing frameshifting. Recent studies have improved understanding and revealed greater complexity regarding long-standing paradigms describing key regulatory steps of translation such as start-site selection and the coupling of transcription and translation. In this review, we describe how bacteria regulate their gene expression at the three translational steps and discuss how translation is used to detect and respond to changes in the cellular environment. Finally, we appraise the costs and benefits of regulation at the translational level in bacteria.
Topics: Adaptation, Physiological; Bacteria; Bacterial Proteins; Protein Biosynthesis
PubMed: 32518156
DOI: 10.1074/jbc.REV120.012742 -
Biomolecules Jan 2020Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence... (Review)
Review
Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence suggests that the ribosome can alter the folding trajectory in many different ways. In this review, we summarize the recent examples of how translation affects folding of single-domain, multiple-domain and oligomeric proteins. The vectorial nature of translation, the spatial constraints of the exit tunnel, and the electrostatic properties of the ribosome-nascent peptide complex define the onset of early folding events. The ribosome can facilitate protein compaction, induce the formation of intermediates that are not observed in solution, or delay the onset of folding. Examples of single-domain proteins suggest that early compaction events can define the folding pathway for some types of domain structures. Folding of multi-domain proteins proceeds in a domain-wise fashion, with each domain having its role in stabilizing or destabilizing neighboring domains. Finally, the assembly of protein complexes can also begin cotranslationally. In all these cases, the ribosome helps the nascent protein to attain a native fold and avoid the kinetic traps of misfolding.
Topics: Animals; Humans; Kinetics; Models, Molecular; Protein Biosynthesis; Protein Domains; Protein Folding; Protein Modification, Translational; Proteins; Ribosomes
PubMed: 31936054
DOI: 10.3390/biom10010097 -
Cold Spring Harbor Perspectives in... Nov 2018One of the last hurdles to quantifying the full central dogma of molecular biology in living cells with single-molecule resolution has been the imaging of single... (Review)
Review
One of the last hurdles to quantifying the full central dogma of molecular biology in living cells with single-molecule resolution has been the imaging of single messenger RNA (mRNA) translation. Here we describe how recent advances in protein tagging and imaging technologies are being used to precisely visualize and quantify the synthesis of nascent polypeptide chains from single mRNA in living cells. We focus on recent applications of repeat-epitope tags and describe how they enable quantification of single mRNA ribosomal densities, translation initiation and elongation rates, and translation site mobility and higher-order structure. Together with complementary live-cell assays to monitor translation using fast-maturing fluorophores and mRNA-binding protein knockoff, single-molecule studies are beginning to uncover striking and unexpected heterogeneity in gene expression at the level of translation.
Topics: Epitopes; Gene Expression Regulation; Humans; Molecular Imaging; Peptide Chain Elongation, Translational; Protein Biosynthesis; RNA, Messenger
PubMed: 30385605
DOI: 10.1101/cshperspect.a032078 -
Progress in Molecular Biology and... 2021Translational control plays a fundamental role in the regulation of gene expression in eukaryotes. Modulating translational efficiency allows the cell to fine-tune the...
Translational control plays a fundamental role in the regulation of gene expression in eukaryotes. Modulating translational efficiency allows the cell to fine-tune the expression of genes, spatially control protein localization, and trigger fast responses to environmental stresses. Translational regulation involves mechanisms acting on multiple steps of the protein synthesis pathway: initiation, elongation, and termination. Many cis-acting elements present in the 5' UTR of transcripts can influence translation at the initiation step. Among them, the Kozak sequence impacts translational efficiency by regulating the recognition of the start codon; upstream open reading frames (uORFs) are associated with inhibition of translation of the downstream protein; internal ribosomal entry sites (IRESs) can promote cap-independent translation. CRISPR-Cas technology is a revolutionary gene-editing tool that has also been applied to the regulation of gene expression. In this chapter, we focus on the genome editing approaches developed to modulate the translational efficiency with the aim to find novel therapeutic approaches, in particular acting on the cis-elements, that regulate the initiation of protein synthesis.
Topics: 5' Untranslated Regions; Gene Editing; Genetic Therapy; Open Reading Frames; Protein Biosynthesis
PubMed: 34175050
DOI: 10.1016/bs.pmbts.2021.01.028 -
Nature Reviews. Cancer Feb 2021
Topics: Humans; Neurons; Pancreatic Neoplasms; Protein Biosynthesis; Serine
PubMed: 33262455
DOI: 10.1038/s41568-020-00324-y -
Cold Spring Harbor Perspectives in... Nov 2018A growing collection of bacterial riboswitch classes is being discovered that sense central metabolites, coenzymes, and signaling molecules. Included among the various... (Review)
Review
A growing collection of bacterial riboswitch classes is being discovered that sense central metabolites, coenzymes, and signaling molecules. Included among the various mechanisms of gene regulation exploited by these RNA regulatory elements are several that modulate messenger RNA (mRNA) translation. In this review, the mechanisms of riboswitch-mediated translation control are summarized to highlight both their diversity and potential ancient origins. These mechanisms include ligand-gated presentation or occlusion of ribosome-binding sites, control of alternative splicing of mRNAs, and the regulation of mRNA stability. Moreover, speculation on the potential for novel riboswitch discoveries is presented, including a discussion on the potential for the discovery of a greater diversity of mechanisms for translation control.
Topics: Animals; Gene Expression Regulation; Protein Biosynthesis; RNA Splicing; Riboswitch
PubMed: 29844057
DOI: 10.1101/cshperspect.a032797 -
Results and Problems in Cell... 2017Germline poses unique challenges to gene expression control at the transcriptional level. While the embryonic germline maintains a global hold on new mRNA transcription,... (Review)
Review
Germline poses unique challenges to gene expression control at the transcriptional level. While the embryonic germline maintains a global hold on new mRNA transcription, the female adult germline produces transcripts that are not translated into proteins until embryogenesis of subsequent generation. As a consequence, translational control plays a central role in governing various germ cell decisions including the formation of primordial germ cells, self-renewal/differentiation decisions in the adult germline, onset of gametogenesis and oocyte maturation. Mechanistically, several common themes such as asymmetric localization of mRNAs, conserved RNA-binding proteins that control translation by 3' UTR binding, translational activation by the cytoplasmic elongation of the polyA tail and the assembly of mRNA-protein complexes called mRNPs have emerged from the studies on Caenorhabditis elegans, Xenopus and Drosophila. How mRNPs assemble, what influences their dynamics, and how a particular 3' UTR-binding protein turns on the translation of certain mRNAs while turning off other mRNAs at the same time and space are key challenges for future work.
Topics: Animals; Female; Gene Expression Regulation; Germ Cells; Humans; Male; Protein Biosynthesis
PubMed: 28247049
DOI: 10.1007/978-3-319-44820-6_6 -
Genomics, Proteomics & Bioinformatics Apr 2016An enormous amount of long non-coding RNAs (lncRNAs) transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is... (Review)
Review
An enormous amount of long non-coding RNAs (lncRNAs) transcribed from eukaryotic genome are important regulators in different aspects of cellular events. Cytoplasm is the residence and the site of action for many lncRNAs. The cytoplasmic lncRNAs play indispensable roles with multiple molecular mechanisms in animal and human cells. In this review, we mainly talk about functions and the underlying mechanisms of lncRNAs in the cytoplasm. We highlight relatively well-studied examples of cytoplasmic lncRNAs for their roles in modulating mRNA stability, regulating mRNA translation, serving as competing endogenous RNAs, functioning as precursors of microRNAs, and mediating protein modifications. We also elaborate the perspectives of cytoplasmic lncRNA studies.
Topics: Animals; Cytoplasm; Humans; MicroRNAs; Phosphorylation; Protein Biosynthesis; RNA Precursors; RNA Stability; RNA, Long Noncoding; Ubiquitination
PubMed: 27163185
DOI: 10.1016/j.gpb.2016.03.005