And to the origin of the ribosome as well.
The ribosome is a relic. It is slow and inefficient, and therefore needed and made in huge amounts in all cells. It is absurdly large, with some of the most highly conserved sequences in all of life and dozens of later additions, ingloriously pasted on the outside. While those later additions are all proteins, its catalytic core is made of RNA, explaining both its age and its slowness. For it is a relic of the RNA world, and itself marks the beginning of the mechanism of protein synthesis that would provide the catalytic capacity to transcend that world. But the ribosome itself would never be superceded, only jury-rigged and augmented. While other molecules like lipids and metabolites are also crucial to biogenesis, this early phase is called the RNA world because RNA is widely thought to be the main catalytic and informational molecule.
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| Schematic of the ribosome, showing decoding on the small subunit, and peptide synthesis on the large subunit (top). Sausage-like tRNAs are shown lining up preparatory step (RF, also called the A site), the transferring step (P), and the exit step (E). The peptidyl transferase core is made of RNA, so all key aspects of this machine are run by RNA. |
So where did the ribosome begin? Its core function is to line up an RNA message that carries the genetic code, to which other RNAs dock, by sequence recognition. These special (transfer RNAs, or tRNAs) have amino acids stuck on their other ends, which then likewise line up and get linked together, forming the nascent protein. It is pretty clear that, while the genetic code now has three nucleotides per unit (codon), enabling 64 possibilities and in fact coding for 20 amino acids, it began with only two, offering 16 possible amino acids. About half of current amino acids are now coded by "degenerate" codons, where the last letter doesn't make any difference- all four (say, GGU, GGC, GGA, GGG, for glycine) code for the same amino acid.
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| A more detailed structure of the ribosome, with RNA shown in thin orange helixes, and proteins shown in teal and green ribbons. The tRNAs are shown in gray (E), orange (P) and purple (A). |
From a great deal of other work, it has been shown to be possible (though whether likely, or inevitable, is another matter) for RNAs to assemble in pre-biotic chemical conditions, and to laboriously operate on each other with catalytic effect, both in polymerization and degradation. Indeed, our mRNA splicing apparatus remains, like the ribosome, based on an RNA catalytic core. And this work suggests that RNAs of some length, like maybe under 100 nucleotides (nt) are plausible, while longer ones would be less plausible. There is some debate about whether in later epochs, the RNA world could have hosted very long RNAs, thereby making up in length and complexity what it generally lacked in conformational precision and chemical versatility. So the question arises- how much is really needed to get to the protein synthesis stage of biogenesis? How might several RNAs have come together to collaborate in this dance of protein synthesis, and what were the minimal requirements?
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| The pseudo-dimeric core of the peptidyl transferase center, pulled out of the larger ribosome structure. This tiny structure is what the current workers attempted to use to simulate very early forms of protein synthesis. |
The site within the ribosome where the single amino acids are linked together (polymerized) is called the peptidyl transferase center. Given properly tRNA-linked acyl-amino acids, it takes only proper steric encouragement, not extra inputs of energy such as ATP, to create the peptide bond. It turns out that the peptidyl transferase center of the ribosome can be thought of as a dimer of two ~ 60 nt long RNAs. Structures of that center show this as the extremely conserved, somewhat kinked helical dimer within all current ribosomes. But can such tiny RNAs do the job? Or do they absolutely require the kind of superstructure in which they are currently embedded?
A recent paper shows that they can do the job by themselves, if very inefficiently.
"The actual reaction occurs within a semi-symmetrical molecular pocket that hosts the A- and P-tRNAs, situated within the peptidyl transferase center (PTC), which provides the sites for the two CCA-tRNA ends. This semi-symmetrical entity provides the framework for optimal positioning of the ribosomal substrates in a favored stereochemistry for peptide bond formation and it confines the void required for the motions associated with protein elongation. The amazingly high conservation of this semi-symmetrical site structure, which seems to be preserved throughout the entire living kingdom, indicates that it is resistant to evolution. Hence, suggesting that it could have existed as a self-folded active entity in the pre-biotic world. Therefore, called by us the protoribosome, i. e. the ancestor of the contemporary ribosome."
The hard part was showing that this is true, which is what two groups have done, one in Japan, one in Israel. They have demonstrated slight amounts of protein synthesis using these tiny RNA molecules, in addition to other RNAs standing in for the code and the tRNAs. This was extremely difficult to do, grinding through the careers of several graduate students and post-docs. The ingredients are as follows: one putative / mini ribosomal RNA of about 71 nt, which forms the dimer of the putative peptide transferase core, and a putative transfer RNA of about 35 nt, which was pre-supplied with an attached amino acid (alanine). Given only those two inputs, they found in the reaction products the dipeptide alanyl-alanine, indicating that one step of synthesis had occurred. The template was a tag of GGU that had been added to the mini-ribosomal RNA, to match the ACCA tail of the mini-tRNA.
So this is a highly unnatural setting, without a true template, and with pre-charged mini-tRNA molecules, and with just-detectable efficacy. But the principle is significant- not only can RNA of relatively simple sorts that we can envision occurring in the RNA world synthesize, cleave, and alter other RNAs, but they can also get to the nascent stage of protein synthesis, one of the bigger hurdles on the way to life as we know it.
