Wobble hypothesis

There are 64 different three-letter codons, but we don t have to have 64 different tRNA molecules. Some of the anticodon loops of some of the tRNAs can recognize (bind to) more than one condon in the mRNA. The anticodon loops of the various tRNAs may also contain modified bases that can read (pair with) multiple normal bases in the RNA. This turns out to be the reason for the wobble hypothesis, in which the first two letters of a codon are more significant than the last letter. Look in a codon table and you ll see that changing the last base in a codon often doesn t change the identity of the amino acid. A tRNA that could recognize any base in codon position 3 would translate all four codons as the same amino acid. If you ve actually bothered to look over a codon table, you realize that it s not quite so simple. Some amino acids have single codons (such as AUG for Met), some amino acids have only two codons, and some have four. 

The "wobble" hypothesis states that the first (5 ) base of the anticodon is not as spatially defined as the other two bases. Movement of that first base allows nontraditional base-pairing with the last (31) base of the codon, thus allowing a single tRNA to recognize more than one codon for a specific amino acid. 

The 3 terminal redundancy of the genetic code and its mechanistic basis were first appreciated by Francis Crick in 1966. He proposed that codons and anticodons interact in an antiparallel manner on the ribosome in such a way as to require strict Watson-Crick pairing (that is, A-U and G-C) in the first two positions of the codon but to allow other pairings in its 3 terminal position. Nonstandard base pairing between the 3 terminal position of the codon and the 5 terminal position of the anticodon alters the geometry between the paired bases Crick s proposal, labeled the wobble hypothesis, is now viewed as correctly describing the codon-anticodon interactions that underlie the translation of the genetic code. 

Crick, F. H. C., Codon-anticodon pairing The wobble hypothesis. J. Mol. Biol. 19 548-555, 1966. A classic paper. 

Explain why the use of GUG and UUG as initiation codons in place of AUG was not expected, even based on Crick s wobble hypothesis. 

Know the principles of the genetic code, the wobble hypothesis, and the concepts of nonsense, missense, and frameshift mutations and how they may be suppressed. 

Table 12.5 Permissible Pairings According to the Wobble Hypothesis...

This can be accounted for by the wobble hypothesis it appears that when a codon in mRNA interacts with the anticodon, unconventional pairing can form between the base in the third position of the codon (3 end of triplet) and the first position of the anticodon. The unusual nucleoside inosine (Chap. 7) frequently occurs in the latter position, and it can pair with A, U, or C. The possibility of more than one type of pairing in this position accounts for the fact that when there is more than one codon for a single amino acid (called synonyms, see Table 17.1), the differences are usually in the third position only. 

Leucine has six codons, the largest number for any amino acid. According to the wobble hypothesis, a single tRNA can accommodate more than one codon. The wobble hypothesis allows for up to three different nucleotides, but only at the third position in the codon, to interact with a single nucleotide in the anticodon. The fact that there are six codons in leucine means that they must differ at positions other than the third, and they therefore could not be accommodated by a single anticodon in a particular tRNA molecule. 

The wobble hypothesis is now firmly established. The anticodons of tRNAs of knovm sequence bind to the codons predicted by this hypothesis. For example, the anticodon of yeast alanyl-tRNA is IGC. This tRNA recognizes the codons... 

Table 29.3. Allowed pairings at the third base of the codon according to the wobble hypothesis...

Shine—Dalgarno sequence (p. 870) peptidyl transferase center (p. 872) wobble hypothesis (p. 874) initiation factor (p. 876) elongation factor Tu (EF-Tu) (p. 876) elongation factor Ts (EF-Ts) (p. 877) elongation factor G (EF-G) (p. 877) release factor (p. 878) signal sequence (p.880)... 

R H. C. Crick. Codon-anticodon pairing the wobble hypothesis. Journal of Molecular Biology, 19 (1966), 548-55. 

The wobble hypothesis, which allows for multiple codon-anticodon interactions by individual tRNAs, is based principally on the following observations ... 

The genetic code is translated through base pairing interactions between mRNA codons and rRNA anticodons. The wobble hypothesis explains why cells usually have fewer tRNAs than expected. 

The best way to conceptualize the principle of the Wobble Hypothesis is from the perspective of the tRNA anticodon, as this emphasizes the use of a single tRNA species to recognize more than one mRNA codon. The first base in the tRNA anticodon corresponds to the last base in the mRNA codon, which is referred to as the wobble position. For example, tRNAs with an inosine in the 50 position of the anticodon have the greatest flexibility and can bind to as many as three different codons (Fig. 26.6). The Wobble Hypothesis was confirmed experimentally... 

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