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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.

SUBMITTER: Caetano-Anolles G

PROVIDER: S-EPMC3749098 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structural phylogenomics retrodicts the origin of the genetic code and uncovers the evolutionary impact of protein flexibility.

Caetano-Anollés Gustavo G Wang Minglei M Caetano-Anollés Derek D

PloS one 20130821 8

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 i ...[more]

PMID: 23991065

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Project description:BACKGROUND: The arrangement of the amino acids in the genetic code is such that neighbouring codons are assigned to amino acids with similar physical properties. Hence, the effects of translational error are minimized with respect to randomly reshuffled codes. Further inspection reveals that it is amino acids in the same column of the code (i.e. same second base) that are similar, whereas those in the same row show no particular similarity. We propose a 'four-column' theory for the origin of the code that explains how the action of selection during the build-up of the code leads to a final code that has the observed properties. RESULTS: The theory makes the following propositions. (i) The earliest amino acids in the code were those that are easiest to synthesize non-biologically, namely Gly, Ala, Asp, Glu and Val. (ii) These amino acids are assigned to codons with G at first position. Therefore the first code may have used only these codons. (iii) The code rapidly developed into a four-column code where all codons in the same column coded for the same amino acid: NUN = Val, NCN = Ala, NAN = Asp and/or Glu, and NGN = Gly. (iv) Later amino acids were added sequentially to the code by a process of subdivision of codon blocks in which a subset of the codons assigned to an early amino acid were reassigned to a later amino acid. (v) Later amino acids were added into positions formerly occupied by amino acids with similar properties because this can occur with minimal disruption to the proteins already encoded by the earlier code. As a result, the properties of the amino acids in the final code retain a four-column pattern that is a relic of the earliest stages of code evolution. CONCLUSION: The driving force during this process is not the minimization of translational error, but positive selection for the increased diversity and functionality of the proteins that can be made with a larger amino acid alphabet. Nevertheless, the code that results is one in which translational error is minimized. We define a cost function with which we can compare the fitness of codes with varying numbers of amino acids, and a barrier function, which measures the change in cost immediately after addition of a new amino acid. We show that the barrier is positive if an amino acid is added into a column with dissimilar properties, but negative if an amino acid is added into a column with similar physical properties. Thus, natural selection favours the assignment of amino acids to the positions that they occupy in the final code.

Project description:BackgroundProteins play a key role in cellular life. They do not act alone but are organised in complexes. Throughout the life of a cell, complexes are dynamic in their composition due to attachments and shared components. Experimental and computational evidence indicate that consecutive addition and secondary losses of components played a major role in the evolution of some complexes, mostly without affecting the core function. Here, we analysed in a large scale approach whether this flexibility in evolution is only limited to a distinct number of complexes or represents a more general trend.ResultsFocussing on human protein complexes, we based our analysis on a manually curated dataset from HPRD. In total, 1,060 complexes with 6,136 proteins from 2,187 unique genes were considered. We computed interologs in 25 different species and predicted the composition of complexes. Over the analysed species, the composition of most complexes was highly flexible and only 25% of all genes were never lost. Even if one component was lost at a particular point in time, the fraction of observed second, independent losses of additional components was high (75% of all complexes affected). Still, loss of whole complexes happened rarely. This biological signal deviated significantly from random models. We exemplified this trend on the anaphase promoting complex (APC) where a core is highly conserved throughout all metazoans, but flexibility in certain components is observable.ConclusionConsecutive additions and losses of distinct units is a fundamental process in the evolution of protein complexes. These evolutionary events affecting genes coding for units in human protein complexes showed a significantly different phylogenetic pattern compared to randomly selected genes. Determination of taxon specific attachments or losses might be linked to specific cellular or morphological features. Thus, protein complexes contain not only structural and functional, but also evolutionary cores.

Project description:There is evidence that the genetic code was established prior to the existence of proteins, when metabolism was powered by ribozymes. Also, early proto-organisms had to rely on simple anaerobic bioenergetic processes. In this work I propose that amino acid fermentation powered metabolism in the RNA world, and that this was facilitated by proto-adapters, the precursors of the tRNAs. Amino acids were used as carbon sources rather than as catalytic or structural elements. In modern bacteria, amino acid fermentation is known as the Stickland reaction. This pathway involves two amino acids: the first undergoes oxidative deamination, and the second acts as an electron acceptor through reductive deamination. This redox reaction results in two keto acids that are employed to synthesise ATP via substrate-level phosphorylation. The Stickland reaction is the basic bioenergetic pathway of some bacteria of the genus Clostridium. Two other facts support Stickland fermentation in the RNA world. First, several Stickland amino acid pairs are synthesised in abiotic amino acid synthesis. This suggests that amino acids that could be used as an energy substrate were freely available. Second, anticodons that have complementary sequences often correspond to amino acids that form Stickland pairs. The main hypothesis of this paper is that pairs of complementary proto-adapters were assigned to Stickland amino acids pairs. There are signatures of this hypothesis in the genetic code. Furthermore, it is argued that the proto-adapters formed double strands that brought amino acid pairs into proximity to facilitate their mutual redox reaction, structurally constraining the anticodon pairs that are assigned to these amino acid pairs. Significance tests which randomise the code are performed to study the extent of the variability of the energetic (ATP) yield. Random assignments can lead to a substantial yield of ATP and maintain enough variability, thus selection can act and refine the assignments into a proto-code that optimises the energetic yield. Monte Carlo simulations are performed to evaluate the establishment of these simple proto-codes, based on amino acid substitutions and codon swapping. In all cases, donor amino acids are assigned to anticodons composed of U+G, and have low redundancy (1-2 codons), whereas acceptor amino acids are assigned to the the remaining codons. These bioenergetic and structural constraints allow for a metabolic role for amino acids before their co-option as catalyst cofactors.

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Structural phylogenomics retrodicts the origin of the genetic code and uncovers the evolutionary impact of protein flexibility.

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Structural phylogenomics retrodicts the origin of the genetic code and uncovers the evolutionary impact of protein flexibility.

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