Eukaryotic translation is the biological process by which messenger RNA is

translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...

into

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s in eukaryotes. It consists of four phases: gene translation, elongation, termination, and recapping.

Initiation

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

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

initiation factor Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis. Initiation factors can interact with repressors to slow down or prevent translation. They have t ...

s, with a special tag bound to the 5'-end of an mRNA molecule, the 5' cap, as well as with the

5' UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of t ...

. These proteins bind the small (40S)

ribosomal Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to for ...

subunit and hold the mRNA in place.

eIF3 Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 co ...

is associated with the 40S ribosomal subunit and plays a role in keeping the large (60S) ribosomal subunit from prematurely binding. eIF3 also interacts with the

eIF4F Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-b ...

complex, which consists of three other initiation factors:

eIF4A The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that ...

eIF4E Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene. Structure and function Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine f ...

, and

eIF4G Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeas ...

is a scaffolding protein that directly associates with both eIF3 and the other two components.

is the cap-binding protein. Binding of the cap by eIF4E is often considered the rate-limiting step of cap-dependent initiation, and the concentration of eIF4E is a regulatory nexus of translational control. Certain viruses cleave a portion of eIF4G that binds eIF4E, thus preventing cap-dependent translation to hijack the host machinery in favor of the viral (cap-independent) messages.

is an ATP-dependent RNA helicase that aids the ribosome by resolving certain secondary structures formed along the mRNA transcript. The

poly(A)-binding protein Poly(A)-binding protein (PAB or PABP) is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on th ...

(PABP) also associates with the

complex via eIF4G, and binds the

poly-A tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...

of most eukaryotic mRNA molecules. This protein has been implicated in playing a role in circularization of the mRNA during translation. This 43S preinitiation complex (43S PIC) accompanied by the protein factors moves along the mRNA chain toward its 3'-end, in a process known as 'scanning', to reach the start codon (typically AUG). In eukaryotes and archaea, the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

encoded by the start codon is methionine. The Met-charged initiator tRNA (Met-tRNA_i^Met) is brought to the P-site of the small ribosomal subunit by eukaryotic initiation factor 2 (eIF2). It hydrolyzes GTP, and signals for the dissociation of several factors from the small ribosomal subunit, eventually leading to the association of the large subunit (or the 60S subunit). The complete ribosome (

80S Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRN ...

) then commences translation elongation. Regulation of protein synthesis is partly influenced by phosphorylation of

eIF2 Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer c ...

(via the α subunit), which is a part of the eIF2-GTP-Met-tRNA_i^Met 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

and inhibits its interactions with

, thus preventing cap-dependent initiation. To oppose the effects of 4EBP, growth factors phosphorylate 4EBP, reducing its affinity for eIF4E and permitting protein synthesis. 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. Additionally, RNA

helicases Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separati ...

such as DHX29 and Ded1/DDX3 may participate in the process of translation initiation, especially for mRNAs with structured 5'UTRs.

Cap-independent initiation

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

internal ribosome entry site An internal ribosome entry site, abbreviated IRES, is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis. In eukaryotic translation, initiation typically occurs at ...

(IRES). Unlike cap-dependent translation, cap-independent translation does not require a 5' cap to initiate scanning from the 5' end of the mRNA until the start codon. The ribosome can localize to the start site by direct binding, initiation factors, and/or ITAFs (IRES trans-acting factors) bypassing the need to scan the entire

. 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.

Elongation

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 N site of the ribosome, which is brought into that site by eIF2, (2) forming the peptide bond, and (3) shifting the mRNA by one codon relative to the ribosome. 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 Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

and

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

). Eukaryotic mRNA precursors must be processed in the

(e.g., capping, polyadenylation, splicing) in ribosomes before they are exported to the

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.

Termination

Termination of elongation depends on eukaryotic release factors. The process is similar to that of bactrial termination, but unlike bactrial termination, there is a universal release factor, eRF1, that recognizes all three stop codons. Upon termination, the ribosome is disassembled and the completed polypeptide is released. eRF3 is a ribosome-dependent GTPase that helps eRF1 release the completed polypeptide. The human genome encodes a few genes whose mRNA stop codon are surprisingly leaky: In these genes, termination of translation is inefficient due to special RNA bases in the vicinity of the stop codon. Leaky termination in these genes leads to translational readthrough of up to 10% of the stop codons of these genes. Some of these genes encode functional

protein domain In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of ...

s in their readthrough extension so that new protein

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

s can arise. This process has been termed 'functional translational readthrough'.

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.

Amino acid substitution

In some cells certain amino acids can be depleted and thus affect translation efficiency. For instance, activated

T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...

secrete

interferon-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

which triggers intracellular tryptophan shortage by upregulating the

indoleamine 2,3-dioxygenase Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO ) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. In humans is encoded by the ''IDO1' ...

1 (IDO1) enzyme. Surprisingly, despite

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...

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 Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

types and have been associated with increased IDO1 expression. Functionally, W>F substitutants can impair

activity.

References

External links

Animation at wku.edu

Animations at nobelprize.org
{{DEFAULTSORT:Eukaryotic Translation Molecular biology Protein biosynthesis Gene expression Eukaryote genetics