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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 -
Molecular Cell Aug 2018The billions of proteins inside a eukaryotic cell are organized among dozens of sub-cellular compartments, within which they are further organized into protein... (Review)
Review
The billions of proteins inside a eukaryotic cell are organized among dozens of sub-cellular compartments, within which they are further organized into protein complexes. The maintenance of both levels of organization is crucial for normal cellular function. Newly made proteins that fail to be segregated to the correct compartment or assembled into the appropriate complex are defined as orphans. In this review, we discuss the challenges faced by a cell of minimizing orphaned proteins, the quality control systems that recognize orphans, and the consequences of excess orphans for protein homeostasis and disease.
Topics: Protein Biosynthesis; Protein Transport; Proteins; Proteolysis; Proteostasis
PubMed: 30075143
DOI: 10.1016/j.molcel.2018.07.001 -
Trends in Neurosciences Jan 2007Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because... (Review)
Review
Compromise of the ubiquitin-proteasome system (UPS) is a potential basis for multiple physiological abnormalities and pathologies in the CNS. This could be because reduced protein turnover leads to bulk intracellular protein accumulation. However, conditions associated with compromised UPS function are also associated with impairments in protein synthesis, and impairment of UPS function is sufficient to inhibit protein synthesis. These data suggest that the toxicity of UPS inhibition need not depend on gross intracellular protein accumulation, and indicate the potential for crosstalk between the UPS and protein-synthesis pathways. In this review, we discuss evidence for interplay between the UPS and protein-synthesis machinery, and outline the implications of this crosstalk for physiological and pathological processes in the CNS.
Topics: Animals; Central Nervous System; Humans; Models, Biological; Protein Biosynthesis; Proteins
PubMed: 17126920
DOI: 10.1016/j.tins.2006.11.003 -
Cold Spring Harbor Perspectives in... Aug 2012
Review
Topics: Endoplasmic Reticulum; Models, Biological; Protein Biosynthesis; Protein Folding
PubMed: 22855729
DOI: 10.1101/cshperspect.a015438 -
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 -
International Journal of Biological... Feb 2022Translation of RNA to protein is a key feature of cellular life. The fidelity of this process mainly depends on the availability of correctly charged tRNAs. Different... (Review)
Review
Translation of RNA to protein is a key feature of cellular life. The fidelity of this process mainly depends on the availability of correctly charged tRNAs. Different domains of tRNA synthetase (aaRS) maintain translation quality by ensuring the proper attachment of particular amino acid with respective tRNA, thus it establishes the rule of genetic code. However occasional errors by aaRS generate mischarged tRNAs, which can become lethal to the cells. Accurate protein synthesis necessitates hydrolysis of mischarged tRNAs. Various cis and trans-editing proteins are identified which recognize these mischarged products and correct them by hydrolysis. Trans-editing proteins are homologs of cis-editing domains of aaRS. The trans-editing proteins work in close association with aaRS, Ef-Tu, and ribosome to prevent global mistranslation and ensures correct charging of tRNA. In this review, we discuss the major trans-editing proteins and compared them with their cis-editing counterparts. We also discuss their structural features, biochemical activity and role in maintaining cellular protein homeostasis.
Topics: Amino Acyl-tRNA Synthetases; Protein Biosynthesis; Protein Modification, Translational; RNA, Transfer
PubMed: 34995670
DOI: 10.1016/j.ijbiomac.2021.12.176 -
Postepy Biochemii 2014Translation initiation is a key rate-limiting step in cellular protein synthesis. A cap-dependent initiation is the most effective mechanism of the translation. However,... (Review)
Review
[Molecular mechanisms of protein biosynthesis initiation--biochemical and biomedical implications of a new model of translation enhanced by the RNA hypoxia response element (rHRE)].
Translation initiation is a key rate-limiting step in cellular protein synthesis. A cap-dependent initiation is the most effective mechanism of the translation. However, some physiological (mitosis) and pathological (oxidative stress) processes may switch the classic mechanism to an alternative one that is regulated by an mRNA element such as IRES, uORF, IRE, CPE, DICE, AURE or CITE. A recently discovered mechanism of RNA hypoxia response element (rHRE)-dependent translation initiation, may change the view of oxygen-regulated translation and give a new insight into unexplained biochemical processes. Hypoxia is one of the better-known factors that may trigger an alternative mechanism of the translation initiation. Temporal events of oxygen deficiency within tissues and organs may activate processes such as angiogenesis, myogenesis, regeneration, wound healing, and may promote an adaptive response in cardiovascular and neurodegenerative diseases. On the other hand, growth of solid tumors may be accompanied by cyclic hypoxia, allowing for synthesis of proteins required for further progression of cancer cells. This paper provides a review of current knowledge on translational control in the context of alternative models of translation initiation.
Topics: Animals; Frameshifting, Ribosomal; Humans; Hypoxia; MicroRNAs; Models, Biological; Neoplasms; Peptide Chain Initiation, Translational; Protein Biosynthesis; RNA; RNA, Messenger; Response Elements
PubMed: 25033541
DOI: No ID Found -
FEMS Microbiology Letters Jan 2003Trans-translation is a process found in all bacteria, which contributes to the release of ribosomes that are stalled through a variety of causes, for example when the 3'... (Review)
Review
Trans-translation is a process found in all bacteria, which contributes to the release of ribosomes that are stalled through a variety of causes, for example when the 3' end of a truncated mRNA lacking a stop codon is reached or at internal clusters of rare codons. Trans-translation requires tmRNA. Trans-translation is not essential for cell viability under laboratory conditions, but recently it has been shown that it can contribute to cell viability in the presence of protein synthesis inhibitors. In this minireview, we consider the connection between trans-translation and antibiotics and the potential of using trans-translation as a therapeutic target.
Topics: Bacteria; Protein Biosynthesis; Protein Synthesis Inhibitors; Ribosomes
PubMed: 12583891
DOI: 10.1111/j.1574-6968.2003.tb11491.x -
Proceedings of the National Academy of... Jan 2022Proteins, as essential biomolecules, account for a large fraction of cell mass, and thus the synthesis of the complete set of proteins (i.e., the proteome) represents a...
Proteins, as essential biomolecules, account for a large fraction of cell mass, and thus the synthesis of the complete set of proteins (i.e., the proteome) represents a substantial part of the cellular resource budget. Therefore, cells might be under selective pressures to optimize the resource costs for protein synthesis, particularly the biosynthesis of the 20 proteinogenic amino acids. Previous studies showed that less energetically costly amino acids are more abundant in the proteomes of bacteria that survive under energy-limited conditions, but the energy cost of synthesizing amino acids was reported to be weakly associated with the amino acid usage in Here we present a modeling framework to estimate the protein cost of synthesizing each amino acid (i.e., the protein mass required for supporting one unit of amino acid biosynthetic flux) and the glucose cost (i.e., the glucose consumed per amino acid synthesized). We show that the logarithms of the relative abundances of amino acids in 's proteome correlate well with the protein costs of synthesizing amino acids (Pearson's = -0.89), which is better than that with the glucose costs (Pearson's = -0.5). Therefore, we demonstrate that tends to minimize protein resource, rather than glucose or energy, for synthesizing amino acids.
Topics: Amino Acids; Biological Evolution; Energy Metabolism; Evolution, Molecular; Metabolic Engineering; Protein Biosynthesis; Proteome; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 35042799
DOI: 10.1073/pnas.2114622119 -
Drug Discovery Today Jun 2019Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The exact cause(s) of PD is not well understood, although genetic mutations are... (Review)
Review
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The exact cause(s) of PD is not well understood, although genetic mutations are associated with some forms of the disease. Many of these mutations, in particular those that are found in LRRK2, DJ-1, PINK1, and Parkin, are linked to the deregulation of mRNA translation, suggesting that this process is important for the onset of PD. Herein, we highlight recent studies that provide insights into the molecular mechanisms that relate mRNA translation to PD. These studies confirm the central role of translation in PD, emphasising the potential of restoring mRNA translation functionality as a new therapeutic treatment against PD, and providing novel targets for developing new chemical agents to target this disease.
Topics: Animals; Humans; Mutation; Parkinson Disease; Pharmaceutical Preparations; Protein Biosynthesis; RNA, Messenger
PubMed: 30974176
DOI: 10.1016/j.drudis.2019.04.003