Translation Initiation: Molecular Mechanisms in Eukaryotes

Christopher UT Hellen, State University of New York, Brooklyn, New York, USA
Tatyana V Pestova, State University of New York, Brooklyn, New York, USA

Published online: September 2006

DOI: 10.1002/9780470015902.a0005994

Initiation is the first phase in protein synthesis, during which eukaryotic initiation factors assemble an 80S ribosome at an initiation codon of a messenger RNA (mRNA) such that this triplet is base-paired to the CAU anticodon of aminoacylated initiator methionyl-transfer RNA in the ribosomal peptidyl site. Initiation is followed by the elongation phase, in which the 80S ribosome moves along the mRNA, translating the open reading frame into protein.

Keywords: eukaryotic translation initiation factor; messenger ribonucleic acid; ribosome; transfer ribonucleic acid; translation initiation

Figure 1. Schematic model of the pathway of 48S initiation complex formation on a capped eukaryotic messenger ribonucleic acid (mRNA). Dissociation of the 80S ribosome into 40S and 60S subunits is effected by eukaryotic translation initiation factor-1A (eIF1A) and -3 (eIF3; step 1). Aminoacylated initiator methionyl-transfer RNA Met-t RNAMeti, guanosine triphosphate (GTP) and eIF2 form a ternary complex (step 2) that binds with eIF1A and eIF3 to a 40S subunit to form a 43S preinitiation complex (step 3). eIF4F and associated cofactors cooperate in adenosine triphosphate (ATP)-dependent binding of the 43S complex to mRNA by creating an unstructured cap-proximal ribosomal binding site (step 4). The interaction of the eIF4G subunit of cap-bound eIF4F with the eIF3 component of the 43S complex (indicated by a dashed, double-headed arrow) promotes attachment of the 43S complex to mRNA. The bound 43S complex requires eIF1 to scan downstream on the 5¢ untranslated region (UTR) until it recognizes the initiation codon (step 5). The anticodon of Met-t RNAMeti is base-paired to the initiation codon in the resulting 48S complex.
Figure 2. Schematic model of the pathway of 80S complex formation. Hydrolysis of eIF2-bound GTP in the 48S complex is triggered by eIF5, possibly leading to release of eIF2–guanosine diphosphate (GDP; step 6). The stage at which eIF1, eIF1A and eIF3 are released is not known. eIF5B–GTP mediates joining of the resulting complex to a 60S ribosomal subunit (step 7). Ribosome-activated hydrolysis of eIF5B-bound GTP leads to release of eIF5B–GDP to form an 80S ribosome that is competent to begin protein synthesis (step 8). Inactive eIF2–GDP is recycled by eIF2B to eIF2–GTP, which is again competent to bind Met-t RNAMeti (step 9).
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 References
    Das S and Maitra U (2001) Functional significance and mechanism of eIF5-promoted GTP hydrolysis in eukaryotic translation initiation. Progress in Nucleic Acids Research and Molecular Biology 70: 207–231.
    Dever TE (2002) Gene-specific regulation by general translation factors. Cell 108: 545–556.
    book Donahue TF (2000) "Genetic approaches to translation initiation in Saccharomyces cerevisiae". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp. 487–502. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    Gingras A-C, Raught B and Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annual Reviews in Biochemistry 68: 913–963.
    Hellen CUT and Sarnow P (2001) Internal ribosomal entry sites in eukaryotic mRNA molecules. Genes and Development 15: 1593–1612.
    book Hershey JWB and Merrick WC (2000) "Pathway and mechanism of initiation in protein synthesis". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp. 33–88. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    book Hinnebusch A (2000) "Mechanisms and regulation of initiator methionyl-tRNA binding to ribosomes". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp. 185–243. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    Kozak M (1991) Structural features in eukaryotic mRNAs that modulate the initiation of translation. Journal of Biological Chemistry 266: 19867–19870.
    book Pestova TV, Dever TE and Hellen CUT (2000) "Ribosomal subunit joining". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp. 425–444. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    book Sachs A (2000) "Physical and functional interactions between the mRNA cap structure and the poly(A) tail". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp. 447–465. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
 Further Reading
    Asano K, Clayton J, Shalev A and Hinnebusch AG (2000) A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo. Genes and Development 14: 2534–2546.
    Cigan AM, Feng L and Donahue TF (1988) Met-t RNAMeti functions in directing the scanning ribosome to the start site of translation. Science 242: 93–97.
    Hentze MW and Kuhn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proceedings of the National Academy of Sciences of the United States of America 93: 8175–8182.
    Huang HK, Yoon H, Hannig EM and Donahue TF (1997) GTP hydrolysis controls stringent selection of the AUG start codon during translation initiation in Saccharomyces cerevisiae. Genes and Development 11: 2396–2413.
    book Jackson RJ (2000) "A comparative view of initiation site selection mechanisms". In: Sonenberg N, Hershey JWB and Mathews MB (eds.) Translational Control of Gene Expression, pp 127–183. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
    Kozak M (1989) The scanning model for translation: an update. Journal of Cellular Biology 108: 229–241.
    Merrick WC (1992) Mechanism and regulation of eukaryotic protein synthesis. Microbiological Reviews 56: 291–315.
    Pause A, Belsham GJ, Gingras AC, et al. (1994) Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5¢-cap function. Nature 371: 762–767.
    Pestova TV, Borukhov SI and Hellen CUT (1998) Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons. Nature 394: 854–859.
    Spahn CMT, Beckmann R, Eswar N, et al. (2001) Structure of the 80S ribosome from Saccharomyces cerevisiae – tRNA–ribosome and subunit–subunit interactions. Cell 107: 373–386.

Related Sub-Topics:

Basic Cell Biology, Protein, RNA and DNA | Translation and Protein synthesis | Translation of RNA | Translational Regulation
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Article Title: Translation Initiation: Molecular Mechanisms in Eukaryotes
 
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Hellen, Christopher UT, and Pestova, Tatyana V(Sep 2006) Translation Initiation: Molecular Mechanisms in Eukaryotes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005994]