But life as we know it would not exist without the emergence of a functionally diverse subset of proteins with catalytic abilities: enzymes. How then did these integral molecules come to be from such humble beginnings?
Their sheer complexity and exquisite morphology suggest that there must have been some sort of trial and error taking place to form such dynamic, life-giving proteins. Not to mention the vast number of different 3D structural conformations possible from forming these longs strings of amino acids, where each single unit is chosen from a pool of 20 possible amino acids- in just a short 6 amino acid peptide there would be a staggering 64 million possible combinations using that 20 amino acid pool.
What if there was an intermediary? A molecule or molecules that could bridge the gap between an amino acid chain and a tightly folded enzyme? Researchers in the US have suggested that small, seven-amino-acid-long peptides may just do this, aggregating together to allow the formation of proteins with enzyme-like activity.
Experiments carried out at Syracuse University and the University of California provided seven unique peptide chains that underwent self-assembly into amyloid proteins, similar to those seen to form plaques in the brains of Alzheimer’s Disease sufferers.
These amyloids were importantly found to have enzymatic capabilities, catalysing the hydrolysis of ester molecules – a process conserved in many modern day enzymes – and may form the basis of enzyme structure which have paved the way for more complex catalytic proteins.
As such, primitive enzymes from self-assembling fibrils in early evolution may have resembled amyloidogenic proteins. In the lab, researchers added Zn2+ to not only stabilise the fibrils but to enhance the enzymatic process of ester hydrolysis after spontaneous formation. The peptides were carefully designed to establish optimal side-chain interactions and four of the seven original designs were shown to each come together in such a precise fashion which meant they could act as enzymes.
This spontaneous self-assembly goes some way to suggesting the origins of such large and unlikely proteins and indeed that the ability to fold precisely is a process which has been conserved ever since. However, due to the fact that these short peptides resemble amyloid precursors, it looks like we humans may be stuck with our evolutionary link to amyloids – both as contributors to early life and as contributors to diseases like Alzheimer’s.
These findings from across the pond indicate that the current amyloid hypothesis may not represent the fullest picture of this disease, as any catalytic tendencies that plaques may have could further contribute to the neuronal loss and atrophy already mediated through direct amyloid toxicity, summating in a collection of pejorative circumstances.
I hope this has sparked some interest and curiosity, below are some articles on the amyloid cascade hypothesis, the origins of the primordial soup as well as the original article discussed in this post.
Rufo CM, Moroz YS, Moroz OV, Stöhr J, Smith TA, Hu X, DeGrado WF, & Korendovych IV (2014). Short peptides self-assemble to produce catalytic amyloids. Nature chemistry, 6 (4), 303-9 PMID: 24651196
Kolb E (2001). A recipe for primordial soup. Annals of the New York Academy of Sciences, 950, 54-65 PMID: 11797763
Karran E, Mercken M, & De Strooper B (2011). The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nature reviews. Drug discovery, 10 (9), 698-712 PMID: 21852788
Images adapted from Swaminathan: http://www.flickr.com/photos/araswami/471003800/ and Nature Chemistry (2014) doi:10.1038/nchem.1894