Eukaryotic initiation factor

Eukaryotic initiation factors (eIFs) are proteins involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of the functional ribosome around the start codon and also provide regulatory mechanisms in translation initiation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitation complex (PIC). Additional factors of the eIF4F complex (eIF4A, E, and G) recruit the 43S PIC to the five-prime cap structure of messenger RNA to promote ribosomal scanning along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes GTP hydrolysis (or gated phosphate release) by specific initiation factors and initiation factor release, resulting in the 60S ribosomal subunit recruitment to form the 80S ribosome.[1] There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic cells. Eukaryotic translation requires at least twelve eukaryotic initiation factors, described below.[2]

eIF1 & eIF1A

eIF1 and eIF1A both bind to the 40S ribosome subunit-mRNA complex. Together they induce an "open" conformation of the mRNA binding channel, which is crucial for scanning, tRNA delivery, and start codon recognition.[3] In particular, eIF1 dissociation from the 40S subunit is considered to be a key step in start codon recognition.[4]

eIF1 and eIF1A are small proteins (12 and 17 kDa, respectively in yeast) and are both components of the 43S preinitiation complexes (PIC). eIF1 binds near the ribosomal P-site, while eIF1A binds near the A-site, in a manner similar to the structurally and functionally related bacterial counterparts IF3 and IF1, respectively.[5]

eIF2

Main article: eIF2

eIF2 is a GTP-binding protein responsible for bringing the initiator tRNA to the P-site of the pre-initiation complex. It has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs specific for elongation of the polypeptide chain. Once it has placed the initiator tRNA on the AUG start codon in the P-site, it hydrolyzes GTP into GDP, and dissociates. This hydrolysis also signals for the dissociation of eIF3, eIF1, and eIF1A, and allows the large subunit to bind. This signals the beginning of elongation.

eIF2 has three subunits, eIF2-α, β, and γ. The former is of particular importance for cells that may need to turn off protein synthesis globally. When phosphorylated, it sequesters eIF2B (not to be confused with beta), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed.

eIF2α-induced translation repression occurs in reticulocytes when starved for iron. In addition, protein kinase R (PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.

eIF3

Main article: eIF3

eIF3 independently binds the 40S ribosomal subunit, multiple initiation factors, and cellular and viral mRNA.[6]

In mammals, eIF3 is the largest initiation factor, made up of 13 subunits (a-m). It has a molecular weight of ~750 kDa and controls the assembly of 40S ribosomal subunit on mRNA that have a 5' cap or an IRES. eIF3 uses the eIF4F complex, or alternatively during internal initiation, an IRES, to position the mRNA strand near the exit site of the 40s ribosomal subunit, thus promoting the assembly of the pre-initiation complex.

In many human cancers, eIF3 subunits are overexpressed (subunits a, b, c, h, i, and m) and underexpressed (subunits e and f).[7] One potential mechanism to explain this disregulation comes from the finding that eIF3 binds a specific set of cell proliferation regulator mRNA transcripts and regulates their translation.[8] eIF3 also mediates cellular signaling through S6K1 and mTOR/Raptor to effect translational regulation.[9]

eIF4F

Main article: eIF4F

The eIF4F complex is composed of three subunits: eIF4A, eIF4E, and eIF4G. Each subunit has multiple human isoforms and there exist additional eIF4 proteins: eIF4B and eIF4H.

eIF4G is a 175.5-kDa scaffolding protein that interacts with eIF3 and the Poly(A)-binding protein (PABP), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds PABP, which binds the poly(A) tail, potentially circularizing and activating the bound mRNA. eIF4A – a DEAD box RNA helicase – is important for resolving mRNA secondary structures.

eIF4B contains two RNA-binding domains – one non-specifically interacts with mRNA, whereas the second specifically binds the 18S portion of the small ribosomal subunit. It acts as an anchor, as well as a critical co-factor for eIF4A. It is also a substrate of S6K, and when phosphorylated, it promotes the formation of the pre-initiation complex. In vertebrates, eIF4H is an additional initiation factor with similar function to eIF4B.

eIF5 & eIF5B

eIF5 is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2 and contains the unusual amino acid hypusine.[10]

eIF5B is a GTPase, and is involved in assembly of the full ribosome. It is the functional eukaryotic analog of bacterial IF2.[11]

eIF6

Main article: eIF6

eIF6 performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit.

See also

References

  1. ↑ Jackson, Richard J.; Hellen, Christopher U. T.; Pestova, Tatyana V. (February 2010). "The mechanism of eukaryotic translation initiation and principles of its regulation". Nature Reviews Molecular Cell Biology. 11 (2): 113–127. doi:10.1038/nrm2838. Retrieved 16 December 2014.
  2. ↑ Aitken, Colin E.; Lorsch, Jon R. (2012). "A mechanistic overview of translation initiation in eukaryotes". Nat. Struct. Mol. Biol. 19 (6): 568–576. doi:10.1038/nsmb.2303. PMID 22664984. Retrieved 20 February 2016.
  3. ↑ Passmore, Lori A.; Schmeing, T. Martin; Maag, David; Applefield, Drew J.; Acker, Michael G.; Algire, Mikkel A.; Lorsch, Jon R.; Ramakrishnan, V. (2007). "The Eukaryotic Translation Initiation Factors eIF1 and eIF1A Induce an Open Conformation of the 40S Ribosome". Mol. Cell. 26: 41–50. doi:10.1016/j.molcel.2007.03.018. PMID 17434125. Retrieved 8 March 2016.
  4. ↑ Yuen-Nei, Cheung; Maag, David; Mitchell, Sarah F.; Fekete, Christie A.; Algire, Mikkel A.; Takacs, Julie E.; Shirokikh, Nikolai; Pestova, Tatyana; Lorsch, Jon R.; Hinnebusch, Alan G. (2007). "Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo". Genes Dev. 21 (10): 1217–1230. doi:10.1101/gad.1528307. PMC 1865493Freely accessible. PMID 17504939. Retrieved 8 March 2016.
  5. ↑ Fraser, Christopher S. (2015). "Quantitative studies of mRNA recruitment to the eukaryotic ribosome". Biochimie. 114: 58–71. doi:10.1016/j.biochi.2015.02.017. PMC 4458453Freely accessible. PMID 25742741. Retrieved 6 March 2016.
  6. ↑ Hinnebusch, Alan G. (2006). "eIF3: a versatile scaffold for translation initiation complexes". Trends Biochem. Sci. 31 (10): 553–562. doi:10.1016/j.tibs.2006.08.005. ISSN 0968-0004. PMID 16920360.
  7. ↑ Hershey, John W.B. (2015). "The role of eIF3 and its individual subunits in cancer". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1849: 792–800. doi:10.1016/j.bbagrm.2014.10.005. ISSN 1874-9399. PMID 25450521.
  8. ↑ Lee, Amy S.Y.; Kranusch, Philip J.; Cate, Jamie H.D. (2015). "eIF3 targets cell-proliferation messenger RNAs for translational activation or repression". Nature. 522: 111–114. doi:10.1038/nature14267. ISSN 0028-0836. PMC 4603833Freely accessible. PMID 25849773.
  9. ↑ Holz, Marina K.; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John (2005). "mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events". Cell. 123: 569–580. doi:10.1016/j.cell.2005.10.024. PMID 16286006. Retrieved 1 March 2016.
  10. ↑ Park, Myung Hee (February 2006). "The Post-Translational Synthesis of a Polyamine-Derived Amino Acid, Hypusine, in the Eukaryotic Translation Initiation Factor 5A (eIF5A)". Journal of Biochemistry. 139 (2): 161–9. doi:10.1093/jb/mvj034. PMC 2494880Freely accessible. PMID 16452303.
  11. ↑ Allen, Gregory S.; Frank, Joachim (2006). "Structural insights on the translation initiation complex: ghosts of a universal initiation complex". Mol. Microbiol. 63 (4): 941–950. doi:10.1111/j.1365-2958.2006.05574.x. PMID 17238926. Retrieved 8 March 2016.

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