Thursday, 16 August 2012

Amyloids: the Adam (and Eve) of Protein Evolution?

Greenwald, J., Riek, R. (2012) On the Possible Amyloid Origin of Protein Folds. Journal of Molecular Biology 421 (4-5): 417-426

There are conflicting views on the possible origins of life on this planet and, in the absence of a fossil or genetic record reaching back several billion years, it is only possible to speculate on the probability of each.  

Three main theories are proposed.  The first is that out of the random peptide sequences emerging in a prebiotic world, that is a world before the appearance of organic life, a single protein fold originated which was capable of providing the key functions of life, with all other proteins evolving from this common ancestor.  The second theory is similar but involves the serendipitous creation of several ancestral protein folds which interacted to create a sustainable life system.  In the last proposal, life originated without peptides, as in the “RNA world” hypothesis which was highlighted by Clare in her Feb 2012 post to this blog, and then common ancestor folds evolved within this existing system, either from a single fold or as a set of interacting folds.
This paper examines the first proposal, that of a single common ancestral fold, which may be considered to be the most likely by virtue of being the simplest.  In examining the hypothesis, a list of properties requisite for any common ancestor fold has been developed by (Greenwald, J., Riek, R. (2012)) against which the various folds in contention have been tested.  The common ancestor fold must:
(i)          have a short and simple sequence, since early replication would have been relatively inaccurate,
(ii)        withstand sequence modifications, for the same reason,
(iii)      provide a function which promotes life, giving it a selective advantage,
(iv)       be composed of amino acids which have been shown to generate in abiotic conditions, since by definition biological synthesis had not developed,
(v)        and be amenable to evolution which could extend the functionality of the fold.

These stipulations have been applied across known protein folds to establish a list of candidates to be investigated for their theoretical fit.

The PDB provided several potential common ancestor folds but most could be discarded on the basis that they were either too long for successful replication, they required residues for stabilization that no-one has yet been able to generate in prebiotic lab conditions or they could not provide an obvious selective advantage as isolated peptides.

The most persuasive argument for a common ancestor fold is brought by the peptide amyloids.  An amyloid is a β strand, potentially as short as four residues, which oligomerizes into parallel or anti parallel β sheets which stack on top of each other with indefinite numbers of repeats to form amyloid fibrils.

Image adapted from (Greenwald, J., Riek, R. (2012)).  A view of a four residue amyloid peptide microcrystal from yeast prion SUP35 (PDB 2OLX)

These amyloid fibrils are famously associated with several neurodegenerative conditions, such as Alzheimer’s disease, but there are also so called functional amyloids with productive biological functions.  The fibrils can comprise thousands of repeats of the single peptide and this creates the potential for an impressive degree of complexity to evolve with large concentrations of functional residues allowing high specificity, reactivity and/or binding affinity.  Furthermore, a broad range of functional amyloids are known, exhibiting a diverse functionality which demonstrates that the fold possessed  both an initial selection advantage and the ability to develop further life promoting activities.

This argument demonstrates that amyloids meet all of the initial conditions required of a common ancestor, but Greenwald and Riek go on to explore further characteristics of amyloids which make them persuasive candidates for the originating fold.  

Several amyloid crystal structures have been solved recently, which have illustrated that amyloids can exhibit either dry interfaces, which are highly interlocked, or hydrated interfaces which have twice the distance between β sheets.  The fact that some amyloid fibrils have been demonstrated to employ both interface types as well as the solution of more complex amyloids, adopting structures such as a β solenoid, indicate that from the very simple starting point of a short amyloid peptide, it is possible to evolve structures capable of catalytic action.  

An example of an amyloid in β solenoid structure: HET-s(218-289) prion.  Image adapted from PDB 2RNM.

Repetition within amyloids allows breadth of form and therefore function, but it also allows the peptide to act as a template for the seeding of new amyloids in an established conformation.  This replicative function is illustrated by prions, misfolded proteins based on amyloid structures which can infect healthy proteins and convert them into the diseased form.  Deadly though it is in prions, this ability of amyloids to store and replicate conformational information is a further argument in favour of its survival as a common ancestor.

The inherent danger of this ability to replicate has led to evidence that selection is biased against peptide sequences which are prone to β aggregation and the observation that more complex life forms have fewer proteins with this propensity.  This need not argue against amyloids as a common ancestor, however, since the fold could have initiated the evolution of proteins but become more of a liability as replacement folds evolved which were more complex, specific and less prone to aggregation.

In summary, amyloids not only fulfill all of the immediate requirements of a common ancestor but they also have several other characteristics that recommend them to the role. They can be short, composed of prebiotic residues, provide a range of functions, be amenable to modifications and extension, show a variety of binding surfaces and can self replicate.  In addition they have been shown to withstand all of the predicted conditions of the environment 3.5 billion years ago, namely extremes in temperature, UV radiation and pH.   

Whilst there is no evidence to indicate directly that a single ancestral fold lies behind the universal proteome, it is certainly a fascinating idea and one that has been shown by this paper to be at least possible.

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