But serine and glycine are not exactly the same size as alanine. That's where the "serine paradox" comes in. Glycine is smaller and serine is larger than alanine. Current theory would not predict that molecules that are both larger and smaller than alanine would be a problem for AlaRS.
"The reason we call it a paradox is because none of the other tRNA synthesases have a problem mis-activating both a smaller and a bigger amino acid," said Guo. "Theoretically, the tRNA synthesases should have the most problem recognizing a smaller amino acid, because a smaller one can also go into the binding pocket. The smaller one is easy to understand. Now we explain the bigger one."
Unexpectedly, the new study's results also revealed that within AlaRS's binding pocket the acidic group of Asp235 creates an extra hydrogen bond with the larger serine molecule. This additional bond turns out to be the major force that helps to secure the misplaced serine in the pocket, despite its larger size. However, x-ray analysis showed that Asp235 is also critical for holding the amino group of alanine. Attempts by the Schimmel-Yang lab (and also most likely by eons of evolution) to replace Asp235 with another residue failed. In fact, the scientists found that to make a change that would eliminate the interaction with serine would also impact negatively on the interaction with the correct amino acid, alanine. So, nature developed another solution by creating AlaXp, which is specifically designed to provide a second check and eliminate any serine that is attached to tRNA (Ala).
Together, AlaRS's large, flexible pocket an
|Contact: Keith McKeown|
Scripps Research Institute