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Translational regulation – Definition, Mechanism

What is Translational regulation?

  • Translational regulation plays a crucial role in controlling the levels of proteins synthesized from mRNA. This regulatory process is essential for cellular responses to stress, growth signals, and differentiation. Unlike transcriptional regulation, which affects gene expression at the mRNA synthesis stage, translational regulation directly influences protein concentration, resulting in immediate cellular adjustments.
  • The main focus of translational regulation is on controlling ribosome recruitment to the initiation codon. However, it can also involve modulation of peptide elongation, termination of protein synthesis, or even ribosome biogenesis. While the fundamental principles of translational regulation are conserved across organisms, there are some differences between prokaryotes and eukaryotes in the finer details of this process.
  • Translational regulation primarily affects the initiation of translation, but it also involves two types of regulatory factors: one for proteins and another for short non-coding RNAs. This regulation is vital for coordinating cellular responses to various stimuli, including stressors, growth signals, and differentiation cues. Compared to transcriptional regulation, translational regulation provides a faster cellular response due to its direct control over protein concentration.
  • Various factors influence the rate of protein synthesis, including sex, hormones, cell cycle, growth and development, health status, living environment, and changes in biochemical substances involved in protein synthesis. In prokaryotes, translation and transcription are often coupled, and the speed of protein synthesis is primarily determined by the speed of transcription due to the short lifespan of mRNA. Regulation of translation in prokaryotes can occur through the modulation of transcription, ensuring the appropriate balance between translation products and their demands.
  • Furthermore, the structure and properties of mRNA also play a role in regulating the speed of protein synthesis. Specific elements within mRNA, such as untranslated regions (UTRs), secondary structures, and binding sites for regulatory factors, can affect translation efficiency. These mRNA features can act as additional checkpoints for controlling protein synthesis and fine-tuning gene expression.

In conclusion, translational regulation is a vital process that controls protein synthesis levels by modulating the initiation, elongation, and termination stages of translation. It enables rapid cellular adjustments in response to various stimuli and is critical for maintaining cellular homeostasis. Understanding the mechanisms and factors involved in translational regulation contributes to our knowledge of gene expression and its impact on cellular processes.

Translational Regulation in prokaryotes

Translational regulation is a fundamental process in prokaryotes that controls the various stages of protein synthesis, including initiation, elongation, and termination. Understanding the mechanisms behind translational regulation is crucial for comprehending how gene expression is finely tuned at the translational level.

Initiation

Initiation is the first step in translation, and it is tightly regulated to ensure accurate protein synthesis. The accessibility of ribosomes to the Shine-Dalgarno sequence, a purine-rich region located upstream of the initiation codon, plays a critical role in initiation. This sequence hybridizes with a pyrimidine-rich sequence on the 16S RNA within the 30S bacterial ribosomal subunit. Polymorphisms in this Shine-Dalgarno sequence can affect the efficiency of base-pairing and subsequent protein expression. Initiation factors, such as IF1, IF2, and IF3, also contribute to the regulation of initiation. IF1 binds to the 30S subunit and triggers a conformational change that allows for the binding of IF2 and IF3. IF2 ensures the proper positioning of the initiator tRNAfMet, which carries the 3′-UAC-5′ anticodon, while IF3 proofreads initiation codon base-pairing to prevent non-canonical initiation. The expression levels of these initiation factors are usually in balance with ribosomes. However, under certain conditions like cold-shock experiments, imbalances in the expression of initiation factors have been observed, leading to changes in translational machinery and increased favorability towards translation of specific cold-shock mRNAs.

Elongation

During the elongation phase of translation, regulation primarily occurs through the availability of transfer RNA (tRNA) pools. Reduced tRNA pools can result in diminished translational efficiency. Interestingly, cellular oxygen supply can influence the richness of these tRNA pools and subsequently impact translation elongation.

Termination

Termination, the final step in translation, requires coordinated interactions between release factor proteins, the mRNA sequence, and ribosomes. When a termination codon is encountered, release factors RF-1, RF-2, and RF-3 contribute to the hydrolysis of the growing polypeptide chain, leading to termination. The efficiency of termination is influenced by bases downstream of the stop codon. Certain bases proximal to the stop codon can suppress termination efficiency by reducing the enzymatic activity of the release factors. For example, the termination efficiency of a UAAU stop codon is approximately 80%, while the efficiency of UGAC as a termination signal is only around 7%.

In summary, translational regulation in prokaryotes encompasses various stages, including initiation, elongation, and termination. Through the accessibility of ribosomes, the activity of initiation factors, the availability of tRNA pools, and the coordination of release factors, prokaryotic cells finely control the synthesis of proteins. Understanding these regulatory mechanisms provides insights into how gene expression is modulated at the translational level.

Translational Regulation in Eukaryotes

Translational regulation in eukaryotes is a complex process that involves precise control over initiation, elongation, and termination of protein synthesis. Understanding these regulatory mechanisms is crucial for deciphering gene expression at the translational level.

Initiation

Initiation in eukaryotes differs from prokaryotes in several key aspects. Eukaryotic translation initiation occurs with the assistance of an 80S ribosome, which is larger than the ribosomes found in prokaryotes. The process begins with the binding of the small 40S ribosomal subunit to the 5′ untranslated region (UTR) of mRNA. Unlike prokaryotes that utilize the Shine-Dalgarno sequence, eukaryotes employ a scanning mechanism to find the initiation codon. This scanning mechanism allows for regulation through RNA secondary structures in the upstream region. However, some mRNA molecules possess internal ribosomal entry sites (IRESs) that bypass the inhibitory RNA structures and facilitate initiation at the start codon. The guidance of the pre-initiation complex (PIC) to the 5′ UTR is facilitated by eukaryotic initiation factors (eIFs), which are subunits of the PIC. Down-regulation of certain eIFs can reduce translation initiation by inhibiting cap-dependent initiation, a process involving the binding of eIF4E to the 5′ 7-methylguanylate cap of mRNA. Another crucial player in initiation regulation is eIF2, responsible for coordinating the interaction between the initiator tRNA and the ribosome’s P-site. Phosphorylation of eIF2 is associated with the termination of translation initiation and can be regulated in response to cellular stresses. Different serine kinases, such as GCN2, PERK, PKR, and HRI, detect cellular stresses and respond by slowing translation through eIF2 phosphorylation.

Elongation

In eukaryotic translation elongation, a distinct feature is the separation from transcription, which is coupled in prokaryotes. Eukaryotic elongation factor 2 (eEF2) is a GTP-dependent translocase that moves nascent polypeptide chains within the ribosome. Phosphorylation of threonine 56 inhibits the binding of eEF2 to the ribosome, resulting in translational inhibition. Cellular stressors, such as anoxia, can induce this inhibitory phosphorylation and halt elongation.

Termination

The process of termination in eukaryotes is mechanistically similar to that in prokaryotes. Termination involves the hydrolytic action of release factors eRF1 and eRF3. However, eukaryotic termination is considered leaky due to the competition between release factors and noncoding tRNAs for binding to stop codons. Occasionally, tRNAs can outcompete release factors by partially matching two out of three bases within the stop codon. Regulation at the termination level can be observed in functional translational readthrough, such as in the LDHB gene. This readthrough leads to the production of a distinct protein variant, LDHBx, which carries a peroxisomal targeting signal and localizes to the peroxisome.

In summary, translational regulation in eukaryotes involves intricate control over initiation, elongation, and termination. This regulation is achieved through various mechanisms, including the scanning mechanism for initiation, phosphorylation-dependent control of initiation and elongation factors, and competition between release factors and tRNAs during termination. Understanding these processes sheds light on how gene expression is finely tuned at the translational level in eukaryotic cells.

FAQ

What is translational regulation?

Translational regulation refers to the control and regulation of protein synthesis during the process of translation, where the information encoded in mRNA molecules is translated into protein molecules.

What are the key components involved in translational regulation?

Translational regulation involves various molecular components, including mRNA molecules, ribosomes, initiation factors, elongation factors, and regulatory proteins.

How does translational regulation differ from transcriptional regulation?

Transcriptional regulation involves the control of gene expression at the level of DNA transcription, while translational regulation controls protein synthesis at the level of mRNA translation.

What are the mechanisms of translational regulation?

Translational regulation can occur through various mechanisms, such as modulation of initiation factors, alteration of ribosome binding to mRNA, changes in mRNA stability, regulatory RNA molecules (e.g., microRNAs) that inhibit translation, and post-translational modifications of regulatory proteins.

Why is translational regulation important?

Translational regulation allows cells to quickly respond to environmental changes and regulate gene expression at the post-transcriptional level. It plays a crucial role in controlling protein levels and determining cellular functions.

What are some examples of translational regulatory elements?

Translational regulatory elements include upstream open reading frames (uORFs), RNA secondary structures (e.g., riboswitches), and sequences within the 5′ and 3′ untranslated regions (UTRs) of mRNA molecules.

How do microRNAs regulate translation?

MicroRNAs (miRNAs) are small non-coding RNA molecules that can bind to complementary sequences in the mRNA molecules, leading to translational repression or degradation of the mRNA, thus inhibiting protein synthesis.

Can translational regulation be influenced by external factors?

Yes, translational regulation can be influenced by various external factors such as nutrient availability, growth factors, stress conditions, and signaling pathways. These factors can modulate the activity of translational regulators or directly affect translation initiation.

Are there any diseases associated with dysregulated translational regulation?

Yes, dysregulation of translational regulation has been implicated in several diseases, including cancer, neurodegenerative disorders, and metabolic disorders. Alterations in translational control can lead to abnormal protein synthesis and contribute to disease development.

How is translational regulation studied in research?

Translational regulation is studied using a combination of molecular biology techniques, such as ribosome profiling, RNA sequencing, reporter gene assays, and mutagenesis experiments. These approaches help unravel the underlying mechanisms and identify key regulatory elements involved in translational control.

References

  • Gebauer, F., Hentze, M. Molecular mechanisms of translational control. Nat Rev Mol Cell Biol 5, 827–835 (2004). https://doi.org/10.1038/nrm1488
  • Hershey JW, Sonenberg N, Mathews MB. Principles of translational control: an overview. Cold Spring Harb Perspect Biol. 2012 Dec 1;4(12):a011528. doi: 10.1101/cshperspect.a011528. PMID: 23209153; PMCID: PMC3504442.
  • Kervestin, S., Amrani, N. Translational regulation of gene expression. Genome Biol 5, 359 (2004). https://doi.org/10.1186/gb-2004-5-12-359
  • Eukaryotic Regulation of Translation. (2021, January 4). University of Wisconsin-Milwaukee. https://bio.libretexts.org/@go/page/16494
  • https://www.studysmarter.us/explanations/biology/control-of-gene-expression/translational-regulation/
  • https://www.pearson.com/channels/microbiology/learn/jason/ch-16-central-dogma-gene-regulation/eukaryotic-post-translational-regulation-Bio-1
  • https://www.creative-diagnostics.com/translational-regulation.htm
  • https://cshperspectives.cshlp.org/content/4/12/a011528.full

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