Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

362 Chapter 6: How Cells Read the Genome: From DNA to Protein
Summary
The translation of the nucleotide sequence of an mRNA molecule into protein takes
place in the cytosol on a large ribonucleoprotein assembly called a ribosome. Each
amino acid used for protein synthesis is first attached to a tRNA molecule that recognizes,
by complementary base-pair interactions, a particular set of three nucleotides
(codons) in the mRNA. As an mRNA is threaded through a ribosome, its
sequence of nucleotides is then read from one end to the other in sets of three according
to the genetic code.
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 protein-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.
The RNA World and the Origins of Life
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.