October 15, 2012

Special mechanisms control the accuracy of protein synthesis

  • The accuracy of protein synthesis is controlled by specific mechanisms at each stage.
We know that protein synthesis is generally accurate, because of the consistency that is found when we determine the sequence of a protein. There are few detailed measurements of the error rate in vivo, but it is generally thought to lie in the range of 1 error for every 104 - 105 amino acids incorporated. Considering that most proteins are produced in large quantities, this means that the error rate is too low to have any effect on the phenotype of the cell.
It is not immediately obvious how such a low error rate is achieved. In fact, the nature of discriminatory events is a general issue raised by several steps in gene expression. How do synthetases recognize just the corresponding tRNAs and amino acids? How does a ribosome recognize only the tRNA corresponding to the codon in the A site? How do the enzymes that synthesize DNA or RNA recognize only the base complementary to the template? Each case poses a similar problem: how to distinguish one particular member from the entire set, all of which share the same general features.
Probably any member initially can contact the active center by a random-hit process, but then the wrong members are rejected and only the appropriate one is accepted. The appropriate member is always in a minority (1 of 20 amino acids, 1 of ~40 tRNAs, 1 of 4 bases), so the criteria for discrimination must be strict. The point is that the enzyme must have some mechanism for increasing discrimination from the level that would be achieved merely by making contacts with the available surfaces of the substrates.

Figure 6.8 summarizes the error rates at the steps that can affect the accuracy of protein synthesis.
Errors in transcribing mRNA are rareprobably <106. This is an important stage to control, because a single mRNA molecule is translated into many protein copies. We do not know very much about the mechanisms.
The ribosome can make two types of errors in protein synthesis. It may cause a frameshift by skipping a base when it reads the mRNA (or in the reverse direction by reading a base twice, once as the last base of one codon and then again as the first base of the next codon). These errors are rare, ~105. Or it may allow an incorrect aminoacyl-tRNA to (mis)pair with a codon, so that the wrong amino acid is incorporated. This is probably the most common error in protein synthesis, ~ 5 x 104. It is controlled by ribosome structure and velocity (see 7.15 The ribosome influences the accuracy of translation).
A tRNA synthetase can make two types of error. It can place the wrong amino acid on its tRNA; or it can charge its amino acid with the wrong tRNA. The incorporation of the wrong amino acid is more common, probably because the tRNA offers a larger surface with which the enzyme can make many more contacts to ensure specificity. Aminoacyl-tRNA synthetases have specific mechanisms to correct errors before a mischarged tRNA is released (see 7.11 Synthetases use proofreading to improve accuracy).