9. Translation: From RNA to Protein (1,023;8/27;pre-RL)

Transcription has produced a working copy of a gene's instructions: an mRNA. Once that mRNA has been processed in the nucleus (5'-cap, poly(A) tail, and splicing), it's packaged with proteins and transported through nuclear pores--large channels in the nuclear membrane--into the cytoplasm. The cell must now translate that code, written in the language of RNA, into an entirely different kind of molecule: a protein.

The central problem, then, is how to convert a four letter nucleotide language into a twenty amino acid language. This process is fittingly called translation.

Let me introduce the main actors in this process. An mRNA is going to carry the instructions. Then, a large molecular machine--an RNA-protein complex called a ribosome--will move along that mRNA, matching amino acids to codons using tRNAs ("transfer") as intermediaries. I should mention that the RNAs that comprise the ribosome are called rRNAs ("ribosomal"). But it is the tRNAs that are the translators between the two languages.

The ribosome will read the mRNA three nucleotides at a time, beginning at the start codon and continuing until it reaches a stop codon. As it proceeds, a growing chain of amino acids will emerge from the ribosome.

A quick refresher on the genetic code. Recall that each three-nucleotide codon specifies an amino acid. AUG usually serves as the start codon and specifies the amino acide methionine (Met). Three different codons can serve as stop signals. And because there are 64 possible codons but only 20 amino acids, a given amino acid can be specified by more than one codon.

A codon, however, cannot recognize an amino acid directly. The cell needs something in between that can interact with both and thus serve as an adaptor--just as one might need an adaptor to enable a standard USB plug to connect with a smaller USB-C port.

These adaptors are tRNAs: relatively small molecules with two functional ends. One end carries one specific amino acid. The other end consists of an anticodon that will recognize a complementary codon on the mRNA.

The amino acid attached to the tRNA is what ultimately becomes part of the protein. The idea here is that tRNAs bridge two molecular languages: nucleotides and amino acids. Human cells use roughly fifty kinds of tRNA to read the 61 codons that specify amino acids. One tRNA can sometimes recognize more than one codon, so a separate tRNA is not required for every codon.

The process begins with a tRNA loading enzyme attaching the right amino acid to the right tRNA--that is, the right amino acid based on that tRNA's anticodon. We know which amino acids are associated with which codons based on the codon table we saw in chapter __.

The accuracy of translation depends heavily on this loading step. There are 20 tRNA loading enzymes in the cytoplasm—essentially one for each amino acid. Each recognizes its amino acid and all the tRNAs that should carry it.

The machine that brings this decoding process together is the ribosome, that large molecular machine that rides down an mRNA. As it does, tRNAs enter and move through three neighboring tRNA holding sites, and the protein grows from there.

We'll number these three ports in the ribosome one through three, but with port one on the right and port three on the left. I'm numbering them in reverse order because tRNAs are going to enter from the right (port 1), then move to port 2 (center) and finally to port three (far left) where they will then depart the ribosome.

Let's see exactly what happens when a ribosome starts translating an mRNA.

The first step breaks the pattern I just described. When the ribosome first attaches to and moves down an mRNA it will quickly reach the start codon (AUG, which codes for the amino acid methionine). It positions the start codon at the base of the second, middle port with the second codon of the mRNA positioned at the base of the first port.

Next, many tRNAs with different anticodons will sample the start codon, but only a tRNA with the complementary anticodon (TAC) and the correct amino acid (methionine, Met) will attach to the codon at the base of port 2. The first amino acid of the protein is now in place.

Let's say the second codon of the gene is CGG, which codes for the amino acid leucine (Leu). A tRNA carrying that amino acid and with the anticodon GCC will then attach--anticodon to codon--to the mRNA in port 1. That will position the two amino acids--Met and Leu--right next to each other. The ribosome will then form a chemical bond between the two. We now have a two amino acid protein.

The ribosome then slides down the mRNA by one codon. This now places the first tRNA (lacking its amino acid, which is now attached to the second amino acid) in port 3, where it will be ejected from the ribosome. The second tRNA, carrying the leucine attached to the methionine, in port 2.

This leaves port 1 open for the third tRNA. Once it arrives, it's anticodon binds to the mRNA's third codon, positioning its particular amino acid next to the leucine. The ribosome then forms a chemical bond between the second and third amino acids. We now have a three amino acid protein. This process continues, growing the protein by one amino acid at a time.

When the ribosome reaches the stop codon (which codes for no amino acid), the process stops. Another protein called a release factor enters the ribosome to trigger the release of the finished protein, and the ribosome dissociates from the mRNA.

Now, with translation complete, the cell has turned a linear sequence of nucleotides into a full-length protein. But this process depends on something we've largely taken for granted: that the DNA containing these genes is accessible in the first place. In reality, DNA is tightly packed within the nucleus, and how it is organized plays an important role in determining which genes can be expressed.

In the next chapter, we'll turn to how DNA is packaged--and how that packaging helps control the flow of genetic information.