Eukaryotic translation

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Eukaryotic translation is the biological process by which

eukaryotes
. It consists of four phases: initiation, elongation, termination, and recapping.

Initiation

The process of initiation of translation in eukaryotes.

Translation initiation is the process by which the ribosome and its associated factors bind to an mRNA and are assembled at the start codon. This process is defined as either cap-dependent, in which the ribosome binds initially at the 5' cap and then travels to the stop codon, or as cap-independent, where the ribosome does not initially bind the 5' cap.

Cap-dependent initiation

some of the protein complexes involved in initiation

Initiation of translation usually involves the interaction of certain key proteins, the

5' UTR. These proteins bind the small (40S) ribosomal subunit and hold the mRNA in place.[1]

poly-A tail of most eukaryotic mRNA molecules. This protein has been implicated in playing a role in circularization of the mRNA during translation.[3]

This

80S
) then commences translation elongation.

Regulation of protein synthesis is partly influenced by phosphorylation of eIF2 (via the α subunit), which is a part of the eIF2-GTP-Met-tRNAiMet ternary complex (eIF2-TC). When large numbers of eIF2 are phosphorylated, protein synthesis is inhibited. This occurs under amino acid starvation or after viral infection. However, a small fraction of this initiation factor is naturally phosphorylated. Another regulator is 4EBP, which binds to the initiation factor eIF4E and inhibits its interactions with eIF4G, thus preventing cap-dependent initiation. To oppose the effects of 4EBP, growth factors phosphorylate 4EBP, reducing its affinity for eIF4E and permitting protein synthesis.[citation needed]

While protein synthesis is globally regulated by modulating the expression of key initiation factors as well as the number of ribosomes, individual mRNAs can have different translation rates due to the presence of regulatory sequence elements. This has been shown to be important in a variety of settings including yeast meiosis and ethylene response in plants. In addition, recent work in yeast and humans suggest that evolutionary divergence in cis-regulatory sequences can impact translation regulation.[4] Additionally, RNA helicases such as DHX29 and Ded1/DDX3 may participate in the process of translation initiation, especially for mRNAs with structured 5'UTRs.[5]

Cap-independent initiation

The best-studied example of cap-independent translation initiation in eukaryotes uses the

5' UTR. This method of translation is important in conditions that require the translation of specific mRNAs during cellular stress, when overall translation is reduced. Examples include factors responding to apoptosis and stress-induced responses.[6]

Elongation

The elongation and membrane targeting stages of eukaryotic translation. The ribosome is green and yellow, the tRNAs are dark-blue, and the other proteins involved are light-blue

Elongation depends on

eukaryotic elongation factors. At the end of the initiation step, the mRNA is positioned so that the next codon can be translated during the elongation stage of protein synthesis. The initiator tRNA occupies the P site in the ribosome
, and the A site is ready to receive an aminoacyl-tRNA. During chain elongation, each additional amino acid is added to the nascent polypeptide chain in a three-step microcycle. The steps in this microcycle are (1) positioning the correct aminoacyl-tRNA in the A site of the ribosome, which is brought into that site by eEF1, (2) forming the peptide bond, and (3) shifting the mRNA by one codon relative to the ribosome with the help of eEF2. Unlike bacteria, in which translation initiation occurs as soon as the 5' end of an mRNA is synthesized, in eukaryotes, such tight coupling between transcription and translation is not possible because transcription and translation are carried out in separate compartments of the cell (the nucleus and cytoplasm). Eukaryotic mRNA precursors must be processed in the nucleus (e.g., capping, polyadenylation, splicing) in ribosomes before they are exported to the cytoplasm for translation. Translation can also be affected by ribosomal pausing, which can trigger endonucleolytic attack of the tRNA, a process termed mRNA no-go decay. Ribosomal pausing also aids co-translational folding of the nascent polypeptide on the ribosome, and delays protein translation while it is encoding tRNA. This can trigger ribosomal frameshifting.[7]

Termination

Termination of elongation depends on

isoforms can arise. This process has been termed 'functional translational readthrough'.[8]

Regulation and modification of translation

Translation is one of the key energy consumers in cells, hence it is strictly regulated. Numerous mechanisms have evolved that control and regulate translation in eukaryotes as well as prokaryotes. Regulation of translation can impact the global rate of protein synthesis which is closely coupled to the metabolic and proliferative state of a cell. To delve deeper into this intricate process, scientists typically use a technique known as ribosome profiling.[9] This method enables researchers to take a snapshot of the translatome, showing which parts of the mRNA are being translated into proteins by ribosomes at a given time. Ribosome profiling provides valuable insights into translation dynamics, revealing the complex interplay between gene sequence, mRNA structure, and translation regulation. Expanding on this concept, a more recent development is single-cell ribosome profiling, a technique that allows us to study the translation process at the resolution of individual cells.[10] Single-cell ribosome profiling has the potential to shed light on the heterogeneous nature of cells, leading to a more nuanced understanding of how translation regulation can impact cell behavior, metabolic state, and responsiveness to various stimuli or conditions.

Amino acid substitution

In some cells certain amino acids can be depleted and thus affect translation efficiency. For instance, activated T cells secrete interferon-γ which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Surprisingly, despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. This is achieved by incorporation of phenylalanine instead of tryptophan. The resulting peptides are called W>F "substitutants". Such W>F substitutants are abundant in certain cancer types and have been associated with increased IDO1 expression. Functionally, W>F substitutants can impair protein activity.[11]

See also

References

  1. S2CID 31720000
    .
  2. PMID 11445534
    .
  3. PMID 9702200
    .
  4. PMID 26297486
    .
  5. PMID 19109895
    .
  6. PMID 16238092
    .
  7. PMID 17696878
    .
  8. PMID 27490485
    .
  9. PMID 19213877
    .
  10. PMID 37344592.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  11. PMID 35264796
    .

External links
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