Translation Initiation Usually Occurs Near the First AUG Closest to the 5 End of an mRNA

During the first stage of translation, a ribosome assembles, complexed with an mRNA and an activated initiator tRNA, which is correctly positioned at the start codon. Large and small ribosomal subunits not actively engaged in translation are kept apart by binding of two initiation factors, designated eIF3 and eIF6 in eukaryotes. A translation preinitia-tion complex is formed when the 40S subunit-eIF3 complex is bound by eIF1A and a ternary complex of the Met-tRNA(Met, eIF2, and GTP (Figure 4-25, step 1). Cells can regulate protein synthesis by phosphorylating a serine residue on the eIF2 bound to GDP; the phosphorylated complex is unable to exchange the bound GDP for GTP and cannot bind Met-tRNAjMet, thus inhibiting protein synthesis.

During translation initiation, the 5' cap of an mRNA to be translated is bound by the eIF4E subunit of the eIF4 cap-binding complex. The mRNA-eIF4 complex then associates with the preinitiation complex through an interaction of the eIF4G subunit and eIF3, forming the initiation complex (Figure 4-25, step 2]). The initiation complex then probably slides along, or scans, the associated mRNA as the helicase activity of eIF4A uses energy from ATP hydrolysis to unwind the RNA secondary structure. Scanning stops when the tRNA(Met anticodon recognizes the start codon, which is the first AUG downstream from the 5' end in most eukaryotic mRNAs (step 3). Recognition of the start codon leads to hydrolysis of the GTP associated with eIF2, an irreversible step that prevents further scanning. Selection of the initiating AUG is facilitated by specific surrounding nucleotides called the Kozak sequence, for Marilyn Kozak, who defined it: (5') ACCAUGG (3'). The A preceding the AUG (underlined) and the G immediately following it are the most important nu-cleotides affecting translation initiation efficiency. Once the small ribosomal subunit with its bound Met-tRNA(Met is correctly positioned at the start codon, union with the large (60S) ribosomal subunit completes formation of an 80S ribosome. This requires the action of another factor (eIF5) and hydrolysis

► FIGURE 4-25 Initiation of translation in eukaryotes.

(Inset) When a ribosome dissociates at the termination of translation, the 40S and 60S subunits associate with initiation factors eIF3 and eIF6, forming complexes that can initiate another round of translation. Steps Oand 2 Sequential addition of the indicated components to the 40S subunit-eIF3 complex forms the initiation complex. Step B: Scanning of the mRNA by the associated initiation complex leads to positioning of the small subunit and bound Met-tRNAMet at the start codon. Step 4 Association of the large subunit (60S) forms an 80S ribosome ready to translate the mRNA. Two initiation factors, eIF2 (step D) and eIF5 (step Q) are GTP-binding proteins, whose bound GTP is hydrolyzed during translation initiation. The precise time at which particular initiation factors are released is not yet well characterized. See the text for details. [Adapted from R. Mendez and J. D. Richter, 2001, Nature Rev. Mol. Cell Biol. 2:521.]

eiF2^GTP + Met-tRNAiMet (ternary complex)

Met Q-GTP

Met Q-GTP

Preinitiation complex

Preinitiation complex r eIF4 (cap-binding complex) + mRNA

Met Q-GTP

Met Q-GTP

m'Gppp VT4A

2' structure unwinding, scanning, and start site recognition

Initiation complex

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