Structural Phylogenomics Retrodicts the Origin of the Genetic Code and Uncovers the Evolutionary Impact of Protein Flexibility

Abstract

The genetic code shapes the genetic repository. Its origin has puzzled molecular scientists for over half a century and remains a long-standing mystery. Here we show that the origin of the genetic code is tightly coupled to the history of aminoacyl-tRNA synthetase enzymes and their interactions with tRNA. A timeline of evolutionary appearance of protein domain families derived from a structural census in hundreds of genomes reveals the early emergence of the ‘operational’ RNA code and the late implementation of the standard genetic code. The emergence of codon specificities and amino acid charging involved tight coevolution of aminoacyl-tRNA synthetases and tRNA structures as well as episodes of structural recruitment. Remarkably, amino acid and dipeptide compositions of single-domain proteins appearing before the standard code suggest archaic synthetases with structures homologous to catalytic domains of tyrosyl-tRNA and seryl-tRNA synthetases were capable of peptide bond formation and aminoacylation. Results reveal that genetics arose through coevolutionary interactions between polypeptides and nucleic acid cofactors as an exacting mechanism that favored flexibility and folding of the emergent proteins. These enhancements of phenotypic robustness were likely internalized into the emerging genetic system with the early rise of modern protein structure.

Coding of Class I and II Aminoacyl-tRNA Synthetases

“…The most serious challenge to the various scenarios described in this review is the significant evidence from Koonin’s group [149,171,159–161] and others [53,172] that speciation of the Class I aaRS did not occur until relatively late in the generation of the proteome. Those studies are based on the most current thinking on phylogenetic reconstruction, yet they appear to be inconsistent with a fundamental role for objects like the bi-directional Protozyme gene products near the root of the proteome.…”

Urzymology: Experimental Access to a Key Transition in the Appearance of Enzymes

“…Systematic protein structure classifications, SCOP (54) and CATH (55), fail to identify Urzymes of either aaRS class as ancestral forms (10). However, aaRS Urzymes represent plausible ancestors for a wide spectrum of contemporary proteins.…”

“…rier to accessing early developmental evolution; phylogenetic trees based on multiple sequence alignments representing essentially modern enzymes lose coherence at that stage and do not root in the invariant structural cores (10).…”

The natural history of transfer RNA and its interactions with the ribosome

“…The catalytic domains of classes I and II aaRS enzymes (belonging to SCOP families d.104.1.1 and c.26.1.1, respectively) are the first to appear in the timeline ~3.7 Gy ago (Caetano-Anollés et al, 2013). These domains harbor pre-transfer and post-transfer editing and trans-editing activities.…”