Eukaryotic Translation

Translation of mRNA is highly regulated in multi-cellular eukaryotic organisms, whereas in prokaryotes regulation occurs mainly at the level of transcription.

• There is global regulation of protein synthesis, e.g., in relation to the cell cycle or in response to cellular stresses such as starvation or accumulation of unfolded proteins in the endoplasmic reticulum. Mechanisms include regulation by signal-activated phosphorylation or dephosphorylation of initiation and elongation factors.
• Translation of particular mRNAs may be inhibited by small single-stranded microRNA molecules about 20-22 nucleotides long. MicroRNAs bind via base-pairing to 3' un-translated regions of mRNA along with a protein complex RISC (RNA-induced silencing complex), inhibiting translation and in some cases promoting mRNA degradation.
• Tissue-specific expression of particular genome-encoded microRNAs is an essential regulatory mechanism controlling embryonic development.
• Some forms of cancer are associated with altered expression of microRNAs that regulate synthesis of proteins relevant to cell cycle progression or apoptosis.

Protein factors that mediate and control translation are more numerous in eukaryotes than in prokaryotes. Eukaryotic factors are designated with the prefix " e ".

• Some factors are highly conserved across kingdoms. For example, the eukaryotic elongation factor eEF1A is structurally and functionally similar to the prokaryotic EF-TU (also called EF1A).
• In contrast, eEF1B, the eukaryotic equivalent of the guanine nucleotide exchange factor EF-Ts, is relativelycomplex, having multiple subunits that are subject to regulatory phosphorylation.

Initiation of protein synthesis is much more complex in eukaryotes, and requires a large number of protein factors. Some eukaryotic initiation factors (e.g., eIF3 and eIF4G) serve as scaffolds, with multiple domains that bind other proteins during assembly of large initiation complexes. Usually a pre-initiation complex forms, including several initiation factors along with the small ribosomal subunit and the loaded initiator tRNA, Met-tRNA_i^Met. This then binds to a separate complex that includes mRNA and other initiation factors including ones that interact with the 5' methylguanosine cap and the 3' poly-A tail, structures unique to eukaryotic mRNA. Within this complex mRNA is thought to be circularized via interactions between factors that associate with the 5' cap and with a poly-A binding protein. A simplified diagram of the eukaryotic initiation complex once it has reached the initiation codon is found in the WormBook.

After the initiation complex assembles, it translocates along the mRNA in a process called scanning, until the initiation codon is reached. Scanning is facilitated by eukaryotic initiation factor eIF4A, which functions as an ATP-dependent helicase to unwind mRNA secondary structure while releasing bound proteins. A short sequence of bases adjacent to the AUG initiation codon may aid in recognition of the start site. After the initiation codon is recognized, there is hydrolysis of GTP and release of initiation factors, as the large ribosomal subunit joins the complex and elongation commences.

For a summary diagrams, see Voet & Voet p. 1324, and Figure 1 of the article by Hinnebusch (requires a subscription to TIBS).

Some eukaryotic mRNAs have what is called an internal ribosome entry site (IRES), far from the 5' capped end, at which initiation may occur without the scanning process.

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