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Structural and biochemical basis of protein amyloid evolution

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Understanding the evolution of proteins

By answering the question of whether or not the molecular mechanisms of amyloid formation have been conserved in evolution, researchers with the EU-funded STAMYEV project are laying the groundwork for new ways of treating such diseases as Alzheimer’s, Familial Amyloidotic Polyneuropathy and atherosclerosis.


Protein misfolding and its aggregation into amyloid fibrils is a hallmark of such serious diseases as Alzheimer’s, Familial Amyloidotic Polyneuropathy (FAP) and atherosclerosis. It is well established that amyloid fibrils can be biologically functional, yet it remains unclear why many different proteins, which often assume stable functional quaternary structure under normal conditions, can convert into a common β-sheet rich amyloid aggregate. An important unanswered question, and one that researchers with the EU-funded STAMYEV project looked to answer, is whether or not the molecular mechanisms of amyloid formation have been conserved in evolution. ‘Our aim was to first develop tools and approaches that could be used to study the molecular basis of amyloid propensity of proteins,’ says project researcher Deborah Power. Although there are many studies on the evolution of genes, there is little research on the way the evolution of proteins and changes in protein sequences may alter protein folding, structure and the general characteristics of proteins. ‘We wanted to know why, during evolution, when one takes into account the negative consequences it has on an organism’s health, has amyloid formation been retained or, in some cases, even increased,’ says Power. Apolipoprotein A-I The STAMYEV study targeted two model proteins: apolipoprotein A-I (apoA-I), a cholesterol transporter involved in atherosclerosis and familial amyloidosis, and transthyretin (TTR), a thyroid hormone (TH) transporter that forms amyloid in FAP. The study of apoA-I, involved several modifications of the protein sequence and evaluation of their impact on protein folding and stability. This study included an apoA-I mutant recently identified in apoA-I amyloidosis patients. ‘The apoA-1 mutation is unique in that it has little effect on the overall secondary structure of the protein yet still decreases its stability,’ explains Power. Researchers also noted that several other point mutations in a particular region of the protein, the helix-bundle domain, caused modified aromatic side chain packing relative to the native protein. Within this study, researchers relied on a truncated version of the ApoA-I protein consisting only of its N-terminal region, which is highly stable compared to the highly unstable full-length protein. The studies allowed the research team to validate the use of C-terminally truncated variants as structural models for understanding the stability and amyloid propensity of their full-length counterparts. Transthyretin (TTR) Project researchers also addressed the question of protein evolution and how this influences protein structure and stability. Here, researchers used TTR from the earliest extant vertebrates, the lampreys, and from sea bream, comparing both to human protein. ‘Our thorough comparative analysis of the stability and propensity for amyloid formation of the three evolutionarily distant TTRs revealed that, during evolution from agnathan to humans, TTR gained an affinity not only for THs, but also become more amyloid-prone and, paradoxically, more thermostable,’ says Power. Power notes that these results were completely unexpected, as the more thermostable protein in humans was more amyloid prone. ‘We are now conducting further studies aimed at better understanding the molecular basis of the increased thermos-stability and amyloid propensity of TTR in humans,’ she adds. Better treatments ahead By providing a better understanding of the process underpinning several neurodegenerative diseases common in aging populations, STAMYEV will likely lead to the identification of new and more effective treatments. This is particularly important in Europe, where the average age of the population is shifting upwards. ‘The costs of amyloidogenic diseases to society are considerable in terms of healthcare needs and loss of work, but also because of the negative impact they have on the structure and functioning of societies,’ concludes Power. ‘We expect that the work done as part of the STAMYEV project will form the foundation for future studies directed at inhibiting amyloid formation.’


STAMYEV, neurodegenerative diseases, amyloid formation, protein misfolding

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