To initiate translation, a small ribosomal subunit binds to the mRNA molecule at a start codon (AUG) that is recognized by a unique initiator tRNA molecule. A large ribosomal subunit then binds to complete the ribosome and begin protein synthesis. During this phase, aminoacyl-tRNAs—each bearing a specific amino acid—bind sequentially to the appropriate codons in mRNA through complementary base-pairing between tRNA anticodons and mRNA codons. Each amino acid is added to the C-terminal end of the growing polypeptide in four sequential steps: aminoacyl-tRNA binding, followed by peptide bond formation, followed by two ribosome translocation steps. Elongation factors use GTP hydrolysis both to drive these reactions forward and to improve the accuracy of amino acid selection. The mRNA molecule progresses codon by codon through the ribosome in the 5ʹ-to-3ʹ direction until it reaches one of three stop codons. A release factor then binds to the ribosome, terminating translation and releasing the completed polypeptide.
Eukaryotic and bacterial ribosomes are closely related, despite differences in the number and size of their rRNA and protein components. The rRNA has the dominant role in translation, determining the overall structure of the ribosome, forming the binding sites for the tRNAs, matching the tRNAs to codons in the mRNA, and creating the active site of the peptidyl transferase enzyme that links amino acids together during translation.
In the final steps of protein synthesis, two distinct types of molecular chaperones guide the folding of polypeptide chains. These chaperones, known as hsp60 and hsp70, recognize exposed hydrophobic patches on proteins and serve to prevent the protein aggregation that would otherwise compete with the folding of newly synthesized proteins into their correct three-dimensional conformations. This pro-tein-folding process must also compete with an elaborate quality control mechanism that destroys proteins with abnormally exposed hydrophobic patches. In this case, ubiquitin is covalently added to a misfolded protein by a ubiquitin ligase, and the resulting polyubiquitin chain is recognized by the cap on a proteasome that unfolds the protein and threads it into the interior of the proteasome for proteolytic degradation. A closely related proteolytic mechanism, based on special degradation signals recognized by ubiquitin ligases, is used to determine the lifetimes of many normally folded proteins as well as to remove selected proteins from the cell in response to specific signals.
We have seen that the expression of hereditary information requires extraordinarily complex machinery and proceeds from DNA to protein through an RNA intermediate. This machinery presents a central paradox: if nucleic acids are required to synthesize proteins and proteins are required, in turn, to synthesize nucleic acids, how did such a system of interdependent components ever arise? One view is that an RNA world existed on Earth before modern cells arose (Figure 6–88). According to this hypothesis, RNA both stored genetic information and catalyzed the chemical reactions in primitive cells. Only later in evolutionary time did DNA take over as the genetic material and proteins become the major catalysts and structural components of cells. If this idea is correct, then the transition out of the RNA world was never complete; as we have seen in this chapter, RNA still catalyzes several fundamental reactions in modern-day cells, which can be viewed as molecular fossils from an earlier world.
formed with DNA
Figure 6–88 Time line for the universe, suggesting the early existence of an RNA world of living systems.
The RNA world hypothesis relies on the fact that, among present-day biological molecules, RNA is unique in being able to act as both a carrier of genetic information and as a ribozyme to catalyze chemical reactions. In this section, we discuss these properties of RNA and how they may have been especially important in early cells.