Research Area

Translational Regulation


Overview of Translational Regulation

Translational Regulation

Translational regulation refers to the control of the levels of protein synthesized from its mRNA. Although most examples of control are thought to affect the initiation of translation, there are two types of regulatory factors, one for proteins and one for short non-coding RNAs. This regulation is vastly important to the cellular response to stressors, growth cues, and differentiation. In comparison to transcriptional regulation, it results in much more immediate cellular adjustment through direct regulation of protein concentration. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. While these general concepts are widely conserved, some of the finer details in this sort of regulation have been proven to differ between prokaryotic and eukaryotic organisms.

The rate of protein synthesis in organisms is mainly at the transcriptional level, and then is regulated and controlled in the process of translation. It is affected by many factors such as sex, hormones, cell cycle, growth and development, health status and living environment, as well as the changes of many biochemical substances involved in protein synthesis. Because translation and transcription in prokaryotes are usually coupled and their mRNA lives are short, the speed of protein synthesis is mainly determined by the speed of transcription. Weakening is a way of regulating the speed of translation by affecting transcription in the first place through the excess and inadequacy of translation products. The structure and properties of mRNA can also regulate the speed of protein synthesis.

Translational Regulation in Eukaryotes

  • Initiation
  • The initiation of translation is that eIF-3 binds to 40S subunit and promotes the dissociation of 80S ribosome from 60S subunit. At the same time, eIF-2 binds to Met-tRNAfmet and GTP under the action of coeffective eIF-2, and then binds to 40S subunit and mRNA through the action of eIF-3 and eIF-4C. In addition to eIF-3, eIF-1, eIF-4A and eIF-4B are required for binding of mRNA to 40S small subunits, which are energized by hydrolysis of ATP into ADP and Pi, and are transferred to small subunits by cap binding factors with mRNA. However, no S-D sequence matched to the small subunit 18SRNA was found at the mRNA5 'end. It is currently believed that by cap binding, the mRNA is scanned downstream on a small subunit, enabling the start codon AUG on the mRNA to be fixed in the anti-password position of Met-tRNAfmet for translation initiation.

  • Elongation
  • Compared with prokaryotes, the marked difference in elongation of eukaryotes lies in their separation from transcription. Although prokaryotes can undergo two cell processes simultaneously, the spatial separation provided by the nuclear membrane prevents this coupling in eukaryotes. Eukaryotic elongation factor 2 (eEF2) is an adjustable GTP-dependent translocation enzyme that moves a new polypeptide chain from site A to site P in the ribosome. The phosphorylation of threonine 56 inhibits the binding of eEF2 to ribosomes. It has been demonstrated that cell stressors such as hypoxia induce translation inhibition through this biochemical interaction.

  • Termination
  • The termination of the polypeptide chain is achieved by hydrolysis of the heterodimer composed of the release factor eRF1 and eRF3. In some cases, translation termination is thought to be leaky because non-coding-tRNA may compete with release factors to bind to termination codons. This is possible because two of the three base pairs in the termination codon may occasionally outperform the release factor base paired tRNA.

Prokaryotes and Translation Initiation Complex

The initiation process of E.coli translation initiation complex is described below.

Each mRNA in prokaryotes has its ribosome binding site, a short fragment of 8-13 nucleotides upstream of AUG called the SD sequence. This sequence is complementary to a portion of the 16S rRNA 3'end of the 30S subunit, so the SD sequence is also called the ribosomal binding sequence. This complementarity means that the ribosome can select the correct position of AUG on the mRNA to initiate peptide chain synthesis. The binding reaction is mediated by initiation factor 3 (IF-3), and IF-1 promotes the binding of IF-3 to small subunits, so the IF3-30S subunit-mRNA ternary complex is formed first.

In the presence of initiation factor 2, formylmethionyl initiation tRNA binds to AUG in the mRNA molecule, and IF3 sheds off from the ternary complex to form a pre-30S initiation complex, which requires the participation of GTP and Mg2+.

The 50S subunit 30S is base on precursor complex, while IF2 sheds to form the 70S starting complex, namely 30S subunit-mRNA-50S subunit-mRNA-fMet-tRNA-fmet complex. FMet-tRNA-fmet occupies the peptide acyl site of 50S subunit. The A site, on the other hand, is empty and awaits the entry of the corresponding aminoacyl tRNA at the second codon of the corresponding mRNA, thus entering the elongation.

Role in Disease

Many clinically effective antibiotics work by specifically inhibiting protein synthesis in prokaryotes, which inhibit bacterial growth without damaging human cells. Drugs for the treatment of bacterial infections can be identified by using the differences in protein synthesis between the two groups.

The eIF4E inhibitory protein regulates the initiation of translation by interacting with eIF4E, which in turn regulates the rate of translation. This regulation of eIF4E inhibitory proteins has a profound effect on cell growth, development, cancer, and neurobiology.

In addition, the widespread expression of translational controlled tumor protein(TCTP) in a variety of tumors suggests that TCTP is a potential and valuable diagnostic target for malignant tumors. Specific TCTP inhibitors or neutralizing antibodies also provide new ideas for the treatment of related tumors.

References:

  1. Milón P, Maracci C, Filonava L, et al. Real-time assembly landscape of bacterial 30S translation initiation complex. Nat Struct Mol Biol. 2012,19:609–615.
  2. Johnson G. Interference with phage lambda development by the small subunit of the phage 21 terminase, gp1. Journal of Bacteriology. 1991,173 (9): 2733–2738.
  3. Poole, E. S., Brown, C. M., & Tate, W. P. The identity of the base following the stop codon determines the efficiency of in vivo translational termination in Escherichia coli. The EMBO Journal, 1995; 14(1), 151–158.
  4. López-Lastra, M; Rivas, A; Barría, MI. Protein synthesis in eukaryotes: the growing biological relevance of cap-independent translation initiation. Biological research. 2005, 38 (2–3): 121–46.

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