Translation Is Terminated by Release Factors When a Stop Codon Is Reached

The final stage of translation, like initiation and elongation, requires highly specific molecular signals that decide the fate of the mRNA-ribosome-tRNA-peptidyl complex. Two types of specific protein release factors (RFs) have been discovered. Eukaryotic eRF1, whose shape is similar to that of tRNAs, apparently acts by binding to the ribosomal A site and recognizing stop codons directly. Like some of the initiation and elongation factors discussed previously, the second eukary-otic release factor, eRF3, is a GTP-binding protein. The eRF3-GTP acts in concert with eRF1 to promote cleavage of the peptidyl-tRNA, thus releasing the completed protein ribosome, these extend into the small subunit where the anticodons of the tRNAs in the A and P sites base-pair with codons in the mRNA. (c) View of the face of the small subunit that interacts with the large subunit in (b). Here the tRNA anticodon loops point into the page. The T^CG loops and acceptor stems extend out of the page and the 3' CCA ends of the tRNAs in the A and P sites point downward. Note the close opposition of the acceptor stems of tRNAs in the A and P sites, which allows the amino group of the acylated tRNA in the A site to react with the carboxyl-terminal C of the peptidyl-tRNA in the P site (see Figure 4-19). In the intact ribosome, these are located at the peptidyltransferase active site of the large subunit. [Adapted from M. M. Yusupov et al., 2001, Science 292:883.]

chain (Figure 4-29). Bacteria have two release factors (RF1 and RF2) that are functionally analogous to eRF1 and a GTP-binding factor (RF3) that is analogous to eRF3.

After its release from the ribosome, a newly synthesized protein folds into its native three-dimensional conformation, a process facilitated by other proteins called chaperones (Chapter 3). Additional release factors then promote dissociation of the ribosome, freeing the subunits, mRNA, and terminal tRNA for another round of translation.

We can now see that one or more GTP-binding proteins participate in each stage of translation. These proteins belong to the GTPase superfamily of switch proteins that cycle between a GTP-bound active form and GDP-bound inactive form (see Figure 3-29). Hydrolysis of the bound GTP is thought to cause conformational changes in the GTPase itself or other associated proteins that are critical to various complex molecular processes. In translation initiation, for instance, hydrolysis of eIF2-GTP to eIF2-GDP prevents further scanning of the mRNA once the start site is encountered and allows binding of the large ribosomal subunit to the small subunit (see Figure 4-25, step 3). Similarly, hydrolysis of

eRF1 + eRF3^GTP

eRF1 + eRF3^GTP

Peptidyl-tRNA cleavage eRF1 +eRF3-GDP + P;

▲ FIGURE 4-29 Termination of translation in eukaryotes.

When a ribosome bearing a nascent protein chain reaches a stop codon (UAA, UGA, UAG), release factor eRF1 enters the ribosomal complex, probably at or near the A site together with eRF3-GTP Hydrolysis of the bound GTP is accompanied by cleavage of the peptide chain from the tRNA in the P site and release of the tRNAs and the two ribosomal subunits.

EF2-GTP to EF2-GDP during chain elongation leads to translocation of the ribosome along the mRNA (see Figure 4-26, step 4).

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