The ribosome is one of the most precious relics we have. Not gilded or nicely framed, or even visible to the naked eye, but it shows, in its tiny structure, a past not a few hundred or thousand years ago as do our cultural relics, or many millions of years as do fossil skeletal relics, but a past over four billion years ago, around the very origin of life on Earth. While roughly three hundred quintillion quadrillion ribosomes exist in the biosphere, visualizing even one and understanding its workings has taken decades.
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| Image of a complete ribosome structure. The large subunit RNA is in grey, the small subunit in turquise. Proteins stuck on the outside are purple and deep blue respectively, the 5S accessory RNA is towards the top in deep purple, and one tRNA is visible in the middle in orange. Note how exceedingly convoluted the RNA is. |
Its convoluted RNA is both the contemporary site of protein synthesis in all cells, and a record of an extremely obscure past that preceeds many other key events in the history of cellular, or even pre-cellular, life, like the use of DNA for information storage, and the use of RNA as a temporary copy for that information. But how to read this record? That is a contentious question, which recent papers battle over.
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| Frame from an animation that illustrates the structure and activity of the ribosome. |
An animation from the ribosome wiki page illustrates its basic activities and structure. First, L-shaped tRNAs (dark blue, held by some helper enzymes in light blue) arrive at the cleft between the large subunit (green) and the small subunit (yellow), each bearing their single amino acid. Only the tRNA that matches the mRNA (black) codon held by the small ribosomal subunit gets to stay and lend its cargo to a growing protein chain, which emerges through a lengthy tunnel upwards and out the back of the large subunit. Eventually, since we are in this case making a secreted or membrane-bound protein, the emerging protein chain is captured by an adaptor which sends the whole ribosome over to the endoplasmic reticulum, (wavy black membrane molecules), where it docks to a channel that allows the new protein to be extruded right through the membrane as the rest of it is synthesized.
The main paper (by group A) provides a fascinating story of the origin of the ribosome, from the ground up, using a couple of structural rationales that allow them to deduce which portions of RNA structure come before or after others. The first rule is that existing RNA helices do not get disrupted by later additions. New additions tend to pop out orthogonally, as shown below, into new helices that are attached to the precursor, but don't disrupt its structure. Due to this phenomenon, the linear sequence of a ribosomal RNA is quite difficult to map onto to its three dimensional structure. Researchers tend to make startingly intricate diagrams to do so.
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| Growth of one small segment of ribosomal RNA, from bacteria (E. coli and P. furiosus) to eukaryotes (S. cerevisiae and H. sapiens). In blue is shown the bacterial core structure, to which in archaeal bacteria is added the green extension. Eukaryotes then added the orange and red extensions. Note how the extensions do not alter the preceding structures, but tack on either by lengthening existing helices or popping out orthogonally. |
The second rule concerns interactions that later RNA segments can have with prior ones, the A-minor stabilization effect. While the RNA double helix is relatively stable, it can be further anchored by supportive hydrogen bonds from another base that swings into the minor groove from another helix. Examples are shown below:
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| One type of interaction where an adenosine from another helix (yellow) nestles close to a pre-existing duplex (blue), interacting with it by hydrogen bonds at several points and increasing the overall structural stability. This is one way to make something stable out of a lot of spaghetti-like RNA. |
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| A more complex example of A-minor interactions that come from helix H-86 (yellow, green, brown) into the minor groove of helix H-75 (teal, grey). Note how some of the A bases (brown) are swung out of their own duplex to provide this interaction. Their partner bases have presumably found other interactions in the larger structure. |
These rules make it conceivable to track one's way backward through the current enormous and complicated structure to its earlier precursors. The method can also be validated with a comparison between the eukaryotic and bacterial ribosomal RNAs, which clearly have an ancestral relationship that is reflected in just such structural expansions and new interactions, as shown above.
Another group (B) of researchers begs to differ, however, and published a disparaging paper about how these techniques are subjective and error-prone. This group appears to use more traditional phylogenetic methods, such as sequence comparisons, plus some kind of energy minimization, but claims that even using group A's stated methods, they would come to different conclusions. In particular, the crucial difference is whether the peptidyl transfer center (PTC), which is where protein synthesis from amino acids is actually carried out, was the first bit of the ribosome to exist (group A), or whether another part was primordial, a part that helps the ribosome rock between one tRNA and the next, an essential part of overall mechanism.
While I am no expert and have not delved into the details of each model, I would tentatively side with group A in this spat, and it is a very significant one. Their model of the ribsome beginning as a non-specific protein synthesizer makes sense in many ways. Their methods also make a more sense than sequence or structural stability methods used by group B that are fine for short-range phylogenetic work, but are notoriously off the mark when it comes to deep phylogenies, especially for RNA. group B also has tendecy to self-cite to a fault. On the other hand, whatever method one chooses, group B is right that it is quite a stretch, and perhaps ultimately subjective, how one gets to the very start of the process- the first few helices of RNA that began as the nucleus of the large ribosomal subunit. While an origin at the PTC is a very sensible proposal, even given the structural methods it is hardly incontestable.
Putting aside this conflict, the proposal from group A, which should be regarded as educated speculation, is an elegant model of ribosomal and translational origins. As shown above in the animation, the two ribosomal subunits work together but do very different things. The small subunit holds into the mRNA message, and thus the three-base codon end of each tRNA (technically, the anti-codon loop) which reads the message. The large subunit holds onto the other end of each tRNA, which is charged with an amino acid, catalyzes its polymerization into a growing protein chain, and conducts that chain out through a tunnel that keeps it from gumming up and folding prematurely. Each time translation completes, the two halves of the ribosome separate, indicating their functional and historical independence.
Thus the earliest stages of the proposed scheme have the large and small subunit evolving entirely independently. The primoridal large subunit's peptide transfer center is proposed to have been making uncoded, unspecific mini-proteins or peptides, possibly in a bid to create a cell surface, food storage, or some other function, even waste disposal. It goes without saying that all this assumes the existence of a pre-cellular RNA world, where RNAs have been functioning as enzymes and inheritance units, and perhaps other necessities, for some time. The proto-small subunit is in the simple business of binding to other RNAs, which is not an unlikely scenario.
The second step of the model is the key phase where the various partners come together. A nascent tRNA helix that had been carrying amino acids to the proto-large subunit for non-specific polymerization gains a helical extension that lets it mediate over to the proto-small subunit carrying short coding RNAs. Whether there were exchangeable, readable RNAs (what are now mRNAs) is doubtful at first, but just the ability to make a consistent protein product based on any code available, even the small subunit's own structural RNA, might have been an advantage. While this was happening, the exit tunnel from the peptide transfer center was also lengthening and tightening as the large subunit evolved, preventing fouling of the apparatus by newly made peptides.
Lastly, the small subunit adopted the switchable code mechanism, which made it a generic partner in the protein synthesis, presenting mRNA produced elsewhere. What the virtue of this might have been in an RNA world, without DNA, is a bit hard to understand, but assuming that such RNAs were specially marked, and not just anything floating around, this might have usefully expanded the protein repertoire. Then we are off in normal evoutionary directions, stabilizing the structure with added RNA and proteins, adding a multitude of factors that check-point the process with respect to starting and completing full protein chains, adding energy, allowing docking to membranes, increasing efficiency and fidelity, generating more mRNAs of ever greater complexity, installing DNA as the repository of mRNA codes, etc.
Interested readers are urged to read the original paper, which goes into much more detail about these steps and the various strucures involved. While speculative, this study opens very interesting vistas on the origin of life, on which the ribosome is such a valuable, if cryptic, window.
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