Aminoacyl-tRNA synthetases (aaRSs) are machines that translate genetic messages in the cell by recognizing and linking together cognate amino acids and tRNAs. Their mystery arises because, once translated aaRSs recognize cognate amino acids and cognate tRNAs and link one to the other for use on the ribosome. Thus, they have the unique property of enforcing the rules by which they themselves were translated. This property, known as reflexivity, was described in detail by Douglas Hofstadter in Gödel, Escher, Bach: an Eternal Golden Braid. The aaRS, and especially their ancestral forms, are a quintessential example of a reflexive “strange loop”.
“A strange loop is a hierarchy of levels, each of which is linked to at least one other by some type of relationship. In moving through the levels, one eventually returns to the starting point, i.e., the original level.” —D. Hofstadter
Reciprocity of protein folding and the enforcement of genetic coding
The image on our home page illustrates this strange loop using Escher-like stairways to represent two kinds of rules governing the operation—and evolutionary history—of aaRS•tRNA cognate pairs. One set (green) governs how amino acid side chains guide the folding of translated proteins into a functional, 3D protein. The other set (blue) governs how the folded aaRS then recognize cognate tRNAs to enforce the coding rules specified by the universal codon table. Much of our research is directed toward illuminating these rules and how they emerged from prebiotic chemistry.
Origin and evolution of the Universal Genetic Code
We believe this strange loop accounts for the evolution of the universal genetic code from a single ancestral gene encoding Class I and Class aaRS on its two strands. The two resulting aaRS•tRNA cognate pairs function as molecular AND gates. They differentiated between two original types of amino acids, enabling codon-directed templating of β-strands (101010) and α helices (0001110) in bidirectional pairs with complementary peptides (010101) and (1110001) with distinct catalytic properties and specificities.