Saturday, November 11, 2017

How Did I Get Here? (From the Primordial Soup)

Review of recent speculations about the origins of protein translation.

DNA may be the biological master code, but proteins are the soul of the machine- the shakers and makers that do everything, or almost everything, around a cell. Given how different these chemicals are in their roles and nature, how did they arise in evolution, and come to the indirect but essential relationship they have today? That is the story of translation and the origin of life. One of the exceptions to the current ubiquity of proteins in active roles is the ribosome- seat of protein synthesis- whose catalytic core is RNA throughout. Indeed the only molecule that can do it all- code for information, survive for reasonable lengths of time, (at least under acidic conditions), and do catalytic reactions, is RNA. This has led to a rough consensus that the very beginnings of chemical reproduction and life-ish chemistry began with an "RNA world". This does not exclude other chemicals, like amino acids and membrane-like lipids participating, but they would not be active in the central reproductive and coding operations that characterize life.

Envisioning the addition of DNA is easy. DNA is similar enough to RNA that there are only a couple of alterations needed to make this far more durable form. Copying is also similar enough to whatever mechanism RNA had to copy itself that the transition between the two is relatively straightforward to envision. And of course, RNA remains the universal carrier of transitory codes- between the durable DNA store and the translation system.
The modern flow of biological information: DNA->RNA->protein.

But getting from the RNA world to the protein world of today remains very hard to envision. There has been quite a bit of recent speculation on the matter, presenting several divergent stories for how this key transition came about. It is an interesting time to take a look at the field, even though it is possible that we may never have a definitive, or even consensus, answer.

The first interesting point to make is that copying RNA is intrinsically a perilous and questionable practice. We naturally think of nucleic acid copying with the model of DNA in mind: making the reverse complement by zipper-like Watson-Crick base pairing. This is the strongest form of nucleic acid interaction, and it takes helicases or other energy typically to pry the resulting duplex nucleic acid pair apart. The product of this reaction is also only a reverse complement, not a precise copy of the original. To copy a functional ribozyme, a second reverse complement would be needed to come up with a true copy of the original. This leads several authors to speculate about "direct" RNA copying systems, where the reverse complement is avoided, thereby sparing the system from these two perils, the first of which is actually the more serious. Reverse complementary sequences form a black hole of stable pairing, from which their originators would have a very difficult time extricating themselves under pre-biotic conditions.

One author (Taylor) proposes an obscure set of base pairing bonds, less strong than the Watson-Crick base pairs, that might form a basis for direct instead of reverse copying. This is highly speculative, and such effective pairing is not shown explicitly in the model, or elsewhere to my knowledge. Thankfully, this property plays no role in his model, which goes on to draw on tRNAs as models for an RNA-based adapter that might have originally brought their nucleotide ends to a ribozyme to carry out this parallel replication into direct RNA copies. This naturally leads to an evolution into carrying amino acids, and the replicative ribozyme transforms into a ribosome.
Proposal from Noller for a double-bridging system for RNA replication that uses a minimal system of adapter RNAs, which are then pre-adapted for later use in ribosomal protein synthesis. 

Another author (Noller) later proposed a similar RNA replication mechanism that produces direct copies at the cost of a similarly non-direct mechanism. In this theory, two identical tRNA-like structures serve as the intermediate bridge between the template and product RNAs in an early RNA replicase, cleverly using short (and normal Watson-Crick) base-pairing interactions to build the copied product RNA, triplet by triplet. Again, the proposal of an indirect (not zippering basepair-mediated) mechanism solves the problems of making reverse complement copies and two-stage copying, at the cost of substantial complexity. But it also obviously lays the foundation of the future ribosome, which uses a similarly indirect (tRNA) means to bring amino acids together bit by bit as directed by a coding RNA template.

Not so fast, claims another group (Harish and Caetano-Anolles). They do an exhaustive analysis of the phylogenetic history of all the RNA and protein components of the ribosome, and come to the somewhat startling conclusion that proteins were there from the very start, co-evolving with the ribosomal core and playing roles in the origin of translation. They allude to non-ribosomal peptide synthesis as a possible source for the early portions of this partnership, which seems under-developed. Phylogenetic analysis is notoriously murky at these early times, especially using RNA sequences, and can be confused with conserved functionality. Perhaps most pursuasive, however, is their specific set of findings that various protein and RNA portions of the ribosome each have, as one would expect, a variety of different ages, and that the oldest protein portion is in contact with the oldest RNA portion, at the mRNA decoding and ratcheting region. This implies not only that proteins were very early partners in whatever this ribozyme was at the time, but also that the peptidyl transfer center, previously thought to be the most ancient heart of the ribosome, only came later. They suggest that this complex was at the time an RNA replicase, but avoid saying much about it.

This raises more insistent questions about how useful, large, and ultimately conserved proteins could be devised at a time before the ribosome arrived, and also, if proteins were present, why weren't their superior catalytic capabilities used to engineer the (later-arriving) peptidyl transferase site, instead of the RNA-based mechanism that still exists?

Lastly, a fourth proposal (Ma) takes another approach to the bridging RNA system, proposing that small RNAs were capable of binding amino acids from very early times, and could have been used for a primitive form of templated protein synthesis. Indeed, they may have started out as RNA-bound co-factors for special ribozyme reactions, rather than as units for peptide synthesis at all. But the amino acid carriers then became standardized, and once they exposed an anticodon, could be harnessed into templated protein synthesis, given some energy, perhaps from the "charged" state by which their amino acids were attached. This theory is a tRNA-first class of theory, and leaves a great deal unsaid and unaccounted for, yet has the virtue of simplicity, plus the recognition that amino acids were common in the prebiotic soup, and likely played some kind of important role from early times.

As one can tell, this field is in ferment, with very interesting ideas deployed to explain a momentous transition of which we can see (and feel and experience) the consequences, but have only the most speculative view of its ingredients, key problems, and context. Origin of life research is a little like string theory in that respect, with little hope of experimental validation, premised on a faith that drawing out the consequences of what is known about the world must, (with a little guessing about what is not known), clarify a world that is at its heart remorselessly logical.

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