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Unfolding "nature's origami"

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2 March 2009

Sometimes known as “nature’s origami”, the way that proteins fold is vital to ensuring they function correctly. But researchers at the University of Leeds have discovered this is a ‘hit and miss’ process, with proteins potentially folding wrongly many times before they form the correct structure for their intended purpose.

The body’s proteins carry out numerous functions and play a crucial role in the growth, repair and workings of cells. Sheena Radford, Professor of Structural Molecular Biology at the University of Leeds, says: "There’s a fine balance between a protein folding into the correct shape so that it can carry out its job efficiently and it folding incorrectly, which can lead to disease. Just one wrong step can tip that balance."

Proteins are made of amino acids arranged in a linear chain and the sequence of these amino acids is determined by the gene producing them. How these chains of amino acids are pre-programmed to fold into their correct protein structure is one of the mysteries of life.

The culmination of many years’ work, the collaborative study looked at the Im7 protein, a simple protein which is present in bacteria and has a crucial role to play in ensuring that bacteria do not kill themselves with the toxins they produce.

"Im7 is like an anti-suicide agent," says Professor Radford. "We studied it partly because of its simplicity and partly because of the known evolutionary pressure on the protein to fold correctly to enable the bacteria to survive."

The study has revealed that these proteins misfold en route to their intended structure, and importantly, has shown the forces at work during the folding process. While the chain of amino acids determines which shape a protein needs to take, the researchers discovered that it was the very amino acids central to the protein’s function that were causing the misfolding.

"This breakthrough could have huge implications for understanding the evolution of today’s protein sequences and in determining the balance between heath and disease," says Professor Radford. "It’s fundamental science, but significant for our understanding of the mechanisms at work in the human body."

This research was funded by the Biotechnology and Biological Sciences Research Council, with further support from various organisations including EMBO, the Leverhulme Trust, the Royal Society, and the Medical Research Council. The study was carried out in collaboration with scientists at the University of Cambridge, and the University of Leeds’ School of Physics and Astronomy.

ENDS

Notes to editors

This research is published in the March edition of Nature Structural Molecular Biology in a paper entitled:
The Mechanism of Folding Im7 Reveals Competition between Functional and Kinetic Evolutionary Constraints.

The papers authors are: Claire T Friel, previously of the University of Leeds and now based at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden; D Alastair Smith, previously of the University of Leeds and now CEO of Avacta Group Plc; Michele Vendrulosco, Department of Chemistry, University of Cambridge; Joerg Gsponer, Medical Research Council Laboratory of Molecular Biology, Cambridge and Sheena Radford, University of Leeds.

A full copy of the paper is available to journalists on request.

About the Faculty of Biological Sciences

The Faculty of Biological Sciences at the University of Leeds is one of the largest in the UK, with over 150 academic staff and over 400 postdoctoral fellows and postgraduate students.

The Faculty is ranked 4th in the UK (Nature Journal, 457 (2009) doi:10.1038/457013a) based on results of the 2008 Research Assessment Exercise (RAE). The RAE feedback noted that "virtually all outputs were assessed as being recognized internationally, with many (60%) being internationally excellent or world-leading" in quality. The Faculty’s research grant portfolio totals some £60M and funders include charities, research councils, the European Union and industry. www.fbs.leeds.ac.uk

About the University of Leeds

The University of Leeds is one of the largest higher education institutions in the UK with more than 30,000 students from 130 countries and a turnover of £450m. The University is a member of the Russell Group of research-intensive universities and the 2008 Research Assessment Exercise showed it to be among the top UK research powerhouses. The University's vision is to secure a place among the world's top 50 by 2015. www.leeds.ac.uk

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The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £420M in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.

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