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Results for “Peptide Chain Initiation, Translational”

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PubMed1977

Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins.

The 12,13-epoxytrichothecenes, specific inhibitors of protein synthesis in eukaryotes, can be subdivided further in terms of their mode of action. In addition to the I-type (initiation inhibitors) and E-types (elongation inhibitors), we found that some E-types apparently exhibit inhibition of chain termination at low concentrations. The nature of substituents on C4 may determine the type of inhibitory activity observed.

Centrifugation, Density Gradient↗

PubMed1975

Effect of reduced temperatures on protein synthesis in mouse L cells.

The rate of incorporation of leucine into protein, the rate of polypeptide elongation and termination, and the relative quantity and size of polysomes were analyzed in mouse L cells grown in suspension culture at various temperatures between 0 degrees C and 36 degrees C. Between 10 degrees C and 36 degrees C protein synthesis exhibited two different apparent activation energies (39 kcal/mole, 10-25 degrees C; 14 kcal/mole, 25-36 degrees C), whereas elongation and termination had only one (16 kcal/mole). Below 36 degrees C, the polysome level and size decreased, reaching a minimum of 30% of the control 36 degrees C values at 10 degrees C; below 10 degrees C the level increased again back to control values at 0 degrees C. The polysome decline was time dependent, requiring about 5 hr to reach the equilibrium value. This decline is completely reversible within 60 min, even in the presence of 4 mug/ml of actinomycin D, and even after 15 hr of incubation at the lower temperature. The results suggest that polypeptide initiation is rate limiting, particularly below 25 degrees C; whereas above this temperature, elongation or perhaps some other process may be limiting. These results are quite different from those obtained for E. coli and rabbit reticulocyte protein synthesis.

Animals↗

PubMed1999

Initiation, elongation, and termination strategies in polyketide and polypeptide antibiotic biosynthesis.

Progress in sequence analysis of biosynthetic gene clusters encoding polyketides and nonribosomal peptides and in the reconstitution of in vitro activities continues to reveal new insights into the growth of these natural products' acyl chains, which have been revealed as a series of elongating, covalent, acyl enzyme intermediates on their multimodular scaffolds. Studies that focus on the three stages of natural product biosynthesis - initiation, elongation, and termination - have yielded crucial information on monomer substrate specificity, domain and module portability, and product release mechanisms, all of which are important not only for an understanding of this exquisite enzymatic machinery, but also for the rational construction of new, functional synthetases and synthases that are a goal of combinatorial biosynthesis.

Acylation↗

PubMed1974

Mechanism of inhibition of eukaryotic protein synthesis by trichothecene fungal toxins.

The 12,13-epoxytrichothecenes, a group of sesquiterpenoid fungal antibiotics, inhibit protein synthesis in eukaryotic cells but do not share a common mode of action. Trichodermin stabilizes polyribosomes, prevents their disaggregation by puromycin, and also prevents the release of nascent peptides from ribosomes by puromycin. Nivalenol, T-2 toxin, and verrucarin A cause rapid and almost quantitative breakdown of polyribosomes in H-HeLa cells, a process which is inhibited by anisomycin, cycloheximide, or trichodermin. Similar effects of trichodermin, nivalenol, and verrucarin A are also observed in yeast spheroplasts. We conclude that nivalenol, T-2 toxin, and verrucarin A are potent and highly selective inhibitors of polypeptide chain initiation in eukaryotes, whereas trichodermin inhibits chain elongation and (or) termination. We have compared the structural formulae of various trichothecenes and suggest that the presence of substituents on carbon-15 of the common trichothecene ring may be important in determining the precise modes of action of this group of compounds.

Acremonium↗

PubMed1974

The genetic control of protein synthesis: The haemoglobin model.

The major steps in haemoglobin synthesis in red cell precursors are now worked out and only details of specific mechanisms remain to be filled in. Thus the major steps in the production of a globin chain are the transcription of large-molecular-weight precursor mRNA (Hn RNA) from the appropriate gene, the cleavage of Hn RNA to produce definitive template mRNA which diffuses into the cell cytoplasm, the processes of chain initiation, translation, and termination, and finally the association of subunits to form a stable tetramer. From what little information there is it appears that this complex series of events is controlled at several levels but that the major control mechanisms are mediated in the processes of transcription rather than translation. There is increasing evidence that the chromatin proteins, particularly the acidic proteins, have specific functions in maintaining areas of DNA repressed and the activation of the haemoglobin loci results from complex interactions with external inducers, the nature of which is not yet known. Virtually nothing is known about the factors involved in the switch from the intrauterine to adult haemoglobins although this appears to be a coordinated event throughout the erythropoietic tissue of the fetus. The isolation and characterization of human mRNA has made possible both the study of the function of thalassaemic mRNA in heterologous systems and , more recently, its quantitation in abnormal red-cell precursors. Furthermore the ability to make cDNA using viral re verse transcriptase has made possible the estimation of the number of haemoglobin genes, both in normal human subjects and in those with different forms of thalassaemia and other genetic disorders of haemoglobin production.

Chromosome Mapping↗

PubMed2002

RNA polymerase II conducts a symphony of pre-mRNA processing activities.

RNA polymerase II (RNAP II) and its associated factors interact with a diverse collection of nuclear proteins during the course of precursor messenger RNA synthesis. This growing list of known contacts provides compelling evidence for the existence of large multifunctional complexes, a.k.a. transcriptosomes, within which the biosynthesis of mature mRNAs is coordinated. Recent studies have demonstrated that the unique carboxy-terminal domain (CTD) of the largest subunit of RNAP II plays an important role in recruiting many of these activities to the transcriptional machinery. Throughout the transcription cycle the CTD undergoes a variety of covalent and structural modifications which can, in turn, modulate the interactions and functions of processing factors during transcription initiation, elongation and termination. New evidence suggests that the possibility that interaction of some of these processing factors with the polymerase can affect its elongation rate. Besides the CTD, proteins involved in pre-mRNA processing can interact with general transcription factors (GTFs) and transcriptional activators, which associate with polymerase at promoters. This suggests a mechanism for the recruitment of specific processing activities to different transcription units. This harmonic integration of transcriptional and post-transcriptional activities, many of which once were considered to be functionally isolated within the cell, supports a general model for the coordination of gene expression by RNAP II within the nucleus.

Animals↗

PubMed2003

Divergent tRNA-like element supports initiation, elongation, and termination of protein biosynthesis.

The cricket paralysis virus internal ribosome entry site (IRES) can, in the absence of canonical initiation factors and initiator tRNA (Met-tRNAi), occupy the ribosomal P-site and assemble 80S ribosomes. Here we show that the IRES assembles mRNA-80S ribosome complexes by recruitment of 60S subunits to preformed IRES-40S complexes. Addition of eukaryotic elongation factors eEF1A and eEF2 and aminoacylated elongator tRNAs resulted in the synthesis of peptides, implying that the IRES RNA itself mimics the function of Met-tRNAi in the P-site to trigger the first translocation step without peptide bond formation. IRES-80S complexes that contained a stop codon in the A-site recruited eukaryotic release factor eRF1, resulting in ribosome rearrangements in a surprisingly eEF2-dependent manner. Thus, this P-site-occupying IRES directs the assembly of 80S ribosomes, sets the translational reading frame, and mimics the functions of both Met-tRNAi and peptidyl tRNA to support elongation and termination.

Amino Acid Sequence↗

PubMed1972

Ribosome crystallization in chicken embryos. II. Conditions for the formation of ribosome tetramers in vitro.

Slow cooling of fertilized chicken eggs permits the elongation and termination of nascen(t) polypeptides in the polysomes but prevents the initiation of new protein chains. This leads to polysome disaggregation during the first 30 min of cooling, and to the formation, of a pool of inactive ribosomes prone to crystallization. After 2 hr these ribosomes began to form tetramers, which do not contain any labeled proteins synthesized during cooling. If protein synthesis is inhibited by cycloheximide, added to eggs before cooling, tetramer formation in the embryos is prevented. Puromycin, on the other hand, leads to polysome disassembly and does not prevent tetramer formation. Rapid cooling of explanted embryos after short incubation at 37 degrees C, with or without cycloheximide, largely prevents polysome disaggregation and the formation of tetramers. On the other hand, the addition of puromycin to explanted embryos promotes tetramer formation after rapid cooling. When cooled eggs are rewarmed, tetramers are disassembled into monomers, even if protein synthesis is inhibited. When those embryos were rapidly recooled tetramers reformed spontaneously from tetramer-derived monomers, even in the presence of cycloheximide. We conclude that the formation of tetramers at low temperature is an inherent property of the normal ribosomes.

Animals↗

PubMed1998

Release factor RF-3 GTPase activity acts in disassembly of the ribosome termination complex.

RF3 was initially characterized as a factor that stimulates translational termination in an in vitro assay. The factor has a GTP binding site and shows sequence similarity to elongation factors EF-Tu and EF-G. Paradoxically, addition of GTP abolishes RF3 stimulation in the classical termination assay, using stop triplets. We here show GTP hydrolysis, which is only dependent on the simultaneous presence of RF3 and ribosomes. Applying a new termination assay, which uses a minimessenger RNA instead of separate triplets, we show that GTP in the presence of RF3 stimulates termination at rate-limiting concentrations of RF1. We show that RF3 can substitute for EF-G in RRF-dependent ribosome recycling reactions in vitro. This activity is GTP-dependent. In addition, excess RF3 and RRF in the presence of GTP caused release of nonhydrolyzed fmet-tRNA. This supports previous genetic experiments, showing that RF3 might be involved in ribosomal drop off of peptidyl-tRNA. In contrast to GTP involvement of the above reactions, stimulation of termination with RF2 by RF3 was independent of the presence of GTP. This is consistent with previous studies, indicating that RF3 enhances the affinity of RF2 for the termination complex without GTP hydrolysis. Based on our results, we propose a model of how RF3 might function in translational termination and ribosome recycling.

GTP Phosphohydrolase-Linked Elongation Factors↗

PubMed1971