Biology Department Seminar

The genetic code is translated by two distinct families of aminoacyl-tRNA synthetases (aaRS), whose role is to accelerate two different chemical reactions: activation of the amino acid carboxyl group at the expense of ATP and transfer of the activated acyl group to the 3’ terminus of the cognate tRNA. Although interest in the synthetase field centers mainly on the second of these reactions, we are preoccupied by the first, because in the absence of catalysts the uncatalyzed rate of amino acid activation is 4-5 orders of magnitude slower than that of acyl transfer. Amino acid activation is therefore the defining kinetic barrier in protein synthesis. We propose that by providing this catalytic activity, primordial aaRS could have launched ribosomal protein synthesis and hence natural selection (1,2). We are developing new methods in order to identify and manipulate models for the ancestral synthetases from both classes (2-4). We have observed that conserved sequences previously thought essential for catalytic activity can be deleted without abolishing activity. In this lecture, I’ll describe an extensive series of active fragments containing the active sites of both tryptophanyl- (Class I) and histidyl- (Class II) tRNA synthetases (2,5), among which the smallest contain only 46 residues. These results enable us to examine possible evolutionary pathways leading to enhanced catalytic activity (3), specificity (2), and allosteric function (6,7). References: 1. Carter, C. W., Jr., and Duax, W. L. (2002) Molec. Cell 10, 705-8. 2. Pham, Y., et al. (2007) Molec. Cell 25, 851-62. 3. Pham, Y., et al. (2010) J. Biol. Chem. 285. 4. Li, L., et al. (2011) J. Biol. Chem., Published online. 5. Rodin, A., et al. (2009) J. Molec. Evolution 69, 555-67. 6. Weinreb, V., et al. (2009) Structure 17, 952-64. 7. Cammer, S., and Carter, C. W., Jr. (2010) Bioinformatics 26, 709-14.