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November 15, 2006

Researchers determine that a balance of amino acids determines whether a protein will become elastomeric or amyloid; may have implications for treatment of tissue-degenerative diseases

TORONTO - Researchers at The Hospital for Sick Children have found that specific combinations of the amino acids proline and glycine are responsible for proteins developing into either elastomeric or amyloid fibrils. This research is reported today in the November 15 issue of the journal Structure.

Elastin is a protein that coils and recoils like a spring within the elastic fibres of connective tissue and accounts for the elasticity of structures such as the skin, blood vessels, heart, lungs, intestines, tendons, and ligaments. An amyloid fibril is an inert deposit of proteins which may be found in a variety of organs including the brain, liver, heart, kidney and pancreas. This accumulation of amyloid fibrils is often connected to inherited and acquired disorders like Alzheimer's disease, Parkinson's disease, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease.

“Both elastin and amyloid materials result from the self-organization of proteins into fibrils and are very important to human health and disease,” said Dr. Régis Pomès, study senior author, scientist in Molecular Structure & Function at SickKids, assistant professor of Biochemistry at the University of Toronto and Canada Research Chair in Physical Chemistry. “The molecular basis of the differing physical properties has been poorly understood, but this study uncovers a surprisingly simple relationship between the composition of proteins and their propensity to form one type of fibril or another.”

When the amino acid proline was replaced by the amino acid glycine in elastin-like proteins, amyloid fibrils developed. Using the Pomès’ lab computing cluster, researchers investigated the origin of this effect in a comparative study of similar protein sequences with very different assembly properties.

The analysis of a variety of protein sequences, including those of elastic proteins and amyloids from mammals, fish, reptiles, insects, spiders and wheat, revealed that the composition of proline and glycine is essential in modulating elastic properties.

In a highly predictive manner the threshold at which amyloid formation was reached and elastomeric properties became apparent. This was confirmed by the self-assembly of these peptides into either amyloid or elastin-like fibrils.

“We showed that elastomeric properties cannot develop concurrently with the formation of amyloids,” said Sarah Rauscher, lead author and graduate student at SickKids and the University of Toronto. “Most importantly, we found that the development of amyloid fibrils can be promoted or impeded by manipulating proline and glycine content.”

“This study offers fundamental insights into the molecular basis for the self-organization and function of two important classes of proteins,” said Dr. Fred Keeley, study senior author, senior scientist in Molecular Structure & Function at SickKids, professor in the departments of Biochemistry & Laboratory Medicine and Pathobiology at the University of Toronto and holder of the Heart and Stroke Foundation of Ontario/Robert M. Freedom Chair in Cardiovascular Science. “The potential long-term impact of this work extends beyond a basic understanding of protein structure and function and will have major implications for the design and development of biomimetic materials and therapeutic approaches against neurodegenerative diseases.”

Other members of the research team included Drs. Stéphaine Baud and Ming Miao, both from SickKids. This research was supported by the Heart and Stroke Foundation of Ontario, the Natural Sciences and Engineering Research Council of Canada, the Canada Research Chairs program and SickKids Foundation.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada’s most research-intensive hospital and the largest centre dedicated to improving children’s health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit www.sickkids.ca. SickKids is committed to healthier children for a better world.

For more information, please contact:

Public Affairs
The Hospital for Sick Children
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Toronto, ON
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