Translation initiation in the crenarchaeon Sulfolobus solfataricus: eukaryotic features but bacterial route

2013 ◽  
Vol 41 (1) ◽  
pp. 350-355 ◽  
Author(s):  
Anna La Teana ◽  
Dario Benelli ◽  
Paola Londei ◽  
Udo Bläsi
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Current Knowledge ◽  
Sulfolobus Solfataricus ◽  
Initiation Complex ◽  
Initiation Factors ◽  
Sequence Of Events ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Rate Limiting

The formation of the translation initiation complex represents the rate-limiting step in protein synthesis. Translation initiation in the crenarchaeon Sulfolobus solfataricus depends on several translation IFs (initiation factors), some of which have eukaryal but no bacterial counterparts. In the present paper, we review the current knowledge of the structure, function and evolution of the IFs in S. solfataricus in the context of eukaryotic and bacterial orthologues. Despite similarities between eukaryotic and S. solfataricus IFs, the sequence of events in translation initiation in S. solfataricus follows the bacterial mode.

scholarly journals The rate-limiting step of protein synthesis in vivo and in vitro and the distribution of growing peptides between the puromycinlabile and puromycin-non-labile sites on polyribosomes

1971 ◽  
Vol 122 (3) ◽  
pp. 267-276 ◽  
Author(s):  
D. C. N. Earl ◽  
Susan T. Hindley
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Donor Site ◽  
Peptide Bond ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Donor And Acceptor ◽  
Rate Limiting

1. At 3 min after an intravenous injection of radioactive amino acids into the rat, the bulk of radioactivity associated with liver polyribosomes can be interpreted as growing peptides. 2. In an attempt to identify the rate-limiting step of protein synthesis in vivo and in vitro, use was made of the action of puromycin at 0°C, in releasing growing peptides only from the donor site, to study the distribution of growing peptides between the donor and acceptor sites. 3. Evidence is presented that all growing peptides in a population of liver polyribosomes labelled in vivo are similarly distributed between the donor and acceptor sites, and that the proportion released by puromycin is not an artifact of methodology. 4. The proportion released by puromycin is about 50% for both liver and muscle polyribosomes labelled in vivo, suggesting that neither the availability nor binding of aminoacyl-tRNA nor peptide bond synthesis nor translocation can limit the rate of protein synthesis in vivo. Attempts to alter this by starvation, hypophysectomy, growth hormone, alloxan, insulin and partial hepatectomy were unsuccessful. 5. Growing peptides on liver polyribosomes labelled in a cell-free system in vitro or by incubating hemidiaphragms in vitro were largely in the donor site, suggesting that either the availability or binding of aminoacyl-tRNA, or peptide bond synthesis, must be rate limiting in vitro and that the rate-limiting step differs from that in vivo. 6. Neither in vivo nor in the hemidiaphragm system in vitro was a correlation found between the proportion of growing peptides in the donor site and changes in the rate of incorporation of radioactivity into protein. This could indicate that the intracellular concentration of amino acids or aminoacyl-tRNA limits the rate of protein synthesis and that the increased incorporation results from a rise to a higher but still suboptimum concentration.

scholarly journals O-GlcNAcylation of core components of the translation initiation machinery regulates protein synthesis

2019 ◽  
Vol 116 (16) ◽  
pp. 7857-7866 ◽  
Author(s):  
Xuexia Li ◽  
Qiang Zhu ◽  
Xiaoliu Shi ◽  
Yaxian Cheng ◽  
Xueliu Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Translational Control ◽  
Soft Agar ◽  
Initiation Complex ◽  
Site Specific ◽  
Initiation Factors ◽  
Key Factor ◽  
Core Components

Protein synthesis is essential for cell growth, proliferation, and survival. Protein synthesis is a tightly regulated process that involves multiple mechanisms. Deregulation of protein synthesis is considered as a key factor in the development and progression of a number of diseases, such as cancer. Here we show that the dynamic modification of proteins by O-linked β-N-acetyl-glucosamine (O-GlcNAcylation) regulates translation initiation by modifying core initiation factors eIF4A and eIF4G, respectively. Mechanistically, site-specific O-GlcNAcylation of eIF4A on Ser322/323 disrupts the formation of the translation initiation complex by perturbing its interaction with eIF4G. In addition, O-GlcNAcylation inhibits the duplex unwinding activity of eIF4A, leading to impaired protein synthesis, and decreased cell proliferation. In contrast, site-specific O-GlcNAcylation of eIF4G on Ser61 promotes its interaction with poly(A)-binding protein (PABP) and poly(A) mRNA. Depletion of eIF4G O-GlcNAcylation results in inhibition of protein synthesis, cell proliferation, and soft agar colony formation. The differential glycosylation of eIF4A and eIF4G appears to be regulated in the initiation complex to fine-tune protein synthesis. Our study thus expands the current understanding of protein synthesis, and adds another dimension of complexity to translational control of cellular proteins.

scholarly journals Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

2021 ◽  
Vol 22 (19) ◽  
pp. 10664
Author(s):  
Stacey L. Lehman ◽  
Evan D. Wilson ◽  
Kevin Camphausen ◽  
Philip J. Tofilon
Keyword(s):  
Tumor Cells ◽  
Translation Initiation ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Control Of Gene Expression ◽  
Translational Machinery ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Cap Binding Complex ◽  
Rate Limiting

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.

scholarly journals Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

2016 ◽  
Vol 2016 ◽  
pp. 1-19 ◽  
Author(s):  
Divya Khandige Sharma ◽  
Kamiko Bressler ◽  
Harshil Patel ◽  
Nirujah Balasingam ◽  
Nehal Thakor
Keyword(s):  
Protein Synthesis ◽  
Cancer Progression ◽  
Translation Initiation ◽  
Tumor Development ◽  
Mrna Translation ◽  
Translation Control ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Rate Limiting Step ◽  
Precise Understanding

Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

Regulation of Protein Synthesis by eIF4E in the Brain

2020 ◽  
Author(s):  
Kleanthi Chalkiadaki ◽  
Stella Kouloulia ◽  
Clive R. Bramham ◽  
Christos G. Gkogkas
Keyword(s):  
Protein Synthesis ◽  
Brain Function ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Eukaryotic Mrnas ◽  
Rate Limiting ◽  
The Brain ◽  
Key Pathways

Regulation of gene expression at the level of mRNA translation is crucial for all the functions our brains carry out. eIF4E binds to the 5′-end of eukaryotic mRNAs and dictates the rate-limiting step of cap-dependent initiation. This chapter reviews the key pathways regulating eIF4E function, but also the less studied and novel mechanisms of eIF4E modulation, linked to synaptic plasticity, learning and memory, and nervous system disorders. Understanding how regulation of protein synthesis by eIF4E affects different aspects of brain function is yet elusive.

scholarly journals Inhibition of translation initiation complex formation by GE81112 unravels a 16S rRNA structural switch involved in P-site decoding

2016 ◽  
Vol 113 (16) ◽  
pp. E2286-E2295 ◽  
Author(s):  
Attilio Fabbretti ◽  
Andreas Schedlbauer ◽  
Letizia Brandi ◽  
Tatsuya Kaminishi ◽  
Anna Maria Giuliodori ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Dynamic Equilibrium ◽  
Ribosomal Subunit ◽  
Structural Level ◽  
Initiation Complex ◽  
Stem Loop ◽  
Initiation Factors ◽  
Initiation Phase

In prokaryotic systems, the initiation phase of protein synthesis is governed by the presence of initiation factors that guide the transition of the small ribosomal subunit (30S) from an unlocked preinitiation complex (30S preIC) to a locked initiation complex (30SIC) upon the formation of a correct codon–anticodon interaction in the peptidyl (P) site. Biochemical and structural characterization of GE81112, a translational inhibitor specific for the initiation phase, indicates that the main mechanism of action of this antibiotic is to prevent P-site decoding by stabilizing the anticodon stem loop of the initiator tRNA in a distorted conformation. This distortion stalls initiation in the unlocked 30S preIC state characterized by tighter IF3 binding and a reduced association rate for the 50S subunit. At the structural level we observe that in the presence of GE81112 the h44/h45/h24a interface, which is part of the IF3 binding site and forms ribosomal intersubunit bridges, preferentially adopts a disengaged conformation. Accordingly, the findings reveal that the dynamic equilibrium between the disengaged and engaged conformations of the h44/h45/h24a interface regulates the progression of protein synthesis, acting as a molecular switch that senses and couples the 30S P-site decoding step of translation initiation to the transition from an unlocked preIC to a locked 30SIC state.

scholarly journals eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency

2021 ◽  
Author(s):  
Dan Li ◽  
Jihong Yang ◽  
Xin Huang ◽  
Hongwei Zhou ◽  
Jianlong Wang
Keyword(s):  
Stem Cell ◽  
Translation Initiation ◽  
Translational Control ◽  
Embryonic Stem ◽  
Initiation Factors ◽  
Rate Limiting Step ◽  
Translation Initiation Factors ◽  
Stem Cell Pluripotency ◽  
Rate Limiting ◽  
Transcription Program

Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNAi screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eIF4A2 and defined its mechanistic action through Rps26-independent and -dependent ribosomes in translation initiation activation of mRNAs encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

scholarly journals The eIF4E-binding proteins are modifiers of cytoplasmic eIF4E relocalization during the heat shock response

2009 ◽  
Vol 296 (5) ◽  
pp. C1207-C1217 ◽  
Author(s):  
R. Sukarieh ◽  
N. Sonenberg ◽  
J. Pelletier
Keyword(s):  
Protein Synthesis ◽  
Binding Proteins ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Repressor Proteins ◽  
Shock Response ◽  
Rate Limiting

Stress granules (SGs) arise as a consequence of cellular stress, contain stalled translation preinitiation complexes, and are associated with cell survival during environmental insults. SGs are dynamic entities with proteins relocating into and out of them during stress. Among the repertoire of proteins present in SGs is eukaryotic initiation factor 4E (eIF4E), a translation factor required for cap-dependent translation and that regulates a rate-limiting step for protein synthesis. Herein, we demonstrate that localization of eIF4E to SGs is dependent on the presence of a family of repressor proteins, eIF4E-binding proteins (4E-BPs). Our results demonstrate that 4E-BPs regulate the SG localization of eIF4E.

Targeting the rate limiting step of protein synthesis may provide an alternative approach to overcome the chemoresistance of malignant mesothelioma

2014 ◽  
Vol 229 ◽  
pp. S226
Author(s):  
Stefano Grosso ◽  
Gifty M. George ◽  
Tatyana Chernova ◽  
Xiao Ming Sun ◽  
Fiona A. Murphy ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Malignant Mesothelioma ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Alternative Approach ◽  
Rate Limiting

scholarly journals RELATION OF PROTEIN SYNTHESIS TO THE DIVISION CYCLE IN MAMMALIAN CELL CULTURES

1963 ◽  
Vol 19 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Edwin W. Taylor
Keyword(s):  
Mathematical Model ◽  
Protein Synthesis ◽  
Mitotic Index ◽  
Relative Rate ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Mammalian Cell Cultures ◽  
Inhibition Process ◽  
Rate Limiting ◽  
Logarithmic Growth

Protein synthesis in suspension cultures of human cells in logarithmic growth was inhibited with puromycin or chloramphenicol, and the growth rate and mitotic index were measured as a function of time. The mitotic index remained constant for about 1 hour after addition of inhibitor; this indicates that any protein synthesis necessary for mitosis is completed before the beginning of prophase. For rates of protein synthesis equal to or greater than 0.3 that of untreated cells, the index decreased over a 5- to-7-hour period and then remained constant. The final value of the index relative to that of the uninhibited control was approximately equal to the relative rate of protein synthesis. The period from the end of DNA synthesis to mitosis (G2) was increased by partial inhibition of protein synthesis. A mathematical model of the inhibition process has been formulated which predicts the shape of the mitotic index curves and the increase in the G2 period. An interpretation of the model is that the rate-limiting step is the synthesis of an enzyme which catalyzes the formation of a compound necessary to initiate mitosis.

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