The transition from noncoded to coded protein synthesis: did coding mRNAs arise from stability-enhancing binding partners to tRNA?

Abstract

Background: Understanding the origin of protein synthesis has been notoriously difficult. We have taken as a starting premise Wolf and Koonin's view that "evolution of the translation system is envisaged to occur in a compartmentalized ensemble of replicating, co-selected RNA segments, i.e., in an RNA world containing ribozymes with versatile activities".

Presentation of the hypothesis: We propose that coded protein synthesis arose from a noncoded process in an RNA world as a natural consequence of the accumulation of a range of early tRNAs and their serendipitous RNA binding partners. We propose that, initially, RNA molecules with 3' CCA termini that could be aminoacylated by ribozymes, together with an ancestral peptidyl transferase ribozyme, produced small peptides with random or repetitive sequences. Our concept is that the first tRNA arose in this context from the ligation of two RNA hairpins and could be similarly aminoacylated at its 3' end to become a substrate for peptidyl transfer catalyzed by the ancestral ribozyme. Within this RNA world we hypothesize that proto-mRNAs appeared first simply as serendipitous binding partners, forming complementary base pair interactions with the anticodon loops of tRNA pairs. Initially this may have enhanced stability of the paired tRNA molecules so they were held together in close proximity, better positioning the 3' CCA termini for peptidyl transfer and enhancing the rate of peptide synthesis. If there were a selective advantage for the ensemble through the peptide products synthesized, it would provide a natural pathway for the evolution of a coding system with the expansion of a cohort of different tRNAs and their binding partners. The whole process could have occurred quite unremarkably for such a profound acquisition.

Testing the hypothesis: It should be possible to test the different parts of our model using the isolated contemporary 50S ribosomal subunit initially, and then with RNAs transcribed in vitro together with a minimal set of ribosomal proteins that are required today to support protein synthesis.

Implications of the hypothesis: This model proposes that genetic coding arose de novo from complementary base pair interactions between tRNAs and single-stranded RNAs present in the immediate environment.

Reviewers: This article was reviewed by Eugene Koonin, Rob Knight and Berthold Kastner (nominated by Laura Landweber).

Figure 1

Proposed hairpin duplication origin of tRNA, based on Di Giulio [31-33]. RNA hairpin (left) was specifically aminoacylated with glycine, enabling it to participate in noncoded peptide synthesis. The hairpin monomer was in equilibrium with the partial duplex (middle), which underwent ligation to form a covalently joined molecule possessing an anticodon loop with the anticodon derived from the 3'-terminal CCA sequence of the upstream hairpin. Mutations produced the first tRNA^Gly (far right), also a substrate for noncoded protein synthesis. Subsequent gene duplication and mutation led to a proliferation of tRNA molecules with different amino acid specificities.

Figure 2

Our proposal for the origin of coded protein synthesis. A depiction of the ancestral peptidyl transferase ribozyme as proposed by Bokov and Steinberg [9] with two tRNAs and a serendipitous proto-mRNA binding partner bound to the two tRNA anticodon loops. Adapted from the PDB files of the T. thermophilus 70S ribosome (with tRNAs and mRNA) taken from Voorhees et al. [98]. PDB files rendered using MacPyMol [99].

Figure 3

A detailed scenario for the origin of genetic coding. 1. Synthesis of gly-gly peptide enhanced by a proto-mRNA complementary to the anticodon loops of tRNA^Gly, sets up positive feedback loop to further enhance gly-gly synthesis from two tRNAs^Gly, plus noncoded synthesis of gly-ser from tRNA^Gly and the hairpin specific for serine, respectively. 2. tRNA^Gly undergoes gene duplication, with one copy undergoing mutation of the acceptor stem to produce a tRNA with aminoacylation specificity for serine (ser). As a result, the synthesis of gly-ser is enhanced by the same proto-mRNA that enhances the synthesis of gly-gly. 3. Selection occurs for mutation of the anticodon loop of proto-tRNA^Ser so that the synthesis of gly-ser is specifically enhanced. In this way, each new amino acid incorporated into the genetic code is specified by a different sequence (codon). Complementary proto-mRNA and tRNA anticodon loop sequences are represented by the same colour.

Figure 4

The origin of the small ribosomal subunit as an RNA hairpin acting in trans. A depiction of the proposed decoding hairpin, possibly ancestral to the small ribosomal subunit RNA [54], interacting with tRNAs in the ancestral A and P sites of the ancestral peptidyl transferase ribozyme [9], and a serendipitous proto-mRNA binding partner bound to the tRNA anticodon loops. Note: this view is from the opposite side of the complex to that shown in Figure 2. Adapted from the PDB files of the T. thermophilus 70S ribosome (with tRNAs and mRNA) taken from Voorhees et al. [98]. PDB files rendered using MacPyMol [99].

Figure 5

A duplication-ligation origin of coded protein synthesis. The origin of coded protein synthesis from the duplication of a hairpin-binding ribozyme [8] to form the proposed ancestral peptidyl transferase ribozyme [9] and the duplication of a hairpin possessing a 3'-terminal CCA [30-32,34] to form the first tRNA. Serendipitous binding of a single-stranded RNA (proto-mRNA) complementary to the tRNA anticodon loops enhanced the binding and positioning of the two tRNAs on the peptidyl transferase, and thereby, the rate of peptide synthesis. Adapted from the PDB files of the T. thermophilus 70S ribosome (with tRNAs and mRNA) taken from Voorhees et al. [98]. PDB files rendered using MacPyMol [99].