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Research offers new way to target shape-shifting proteins

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30 August 2011

BBSRC-funded researchers have used a state-of-the-art method to study the structural biology of long protein strands, known as amyloid fibrils, that cause joint pain in kidney dialysis patients. They have uncovered aspects of the interaction between these fibrils and a molecule that can stop their formation. This discovery could lead to new methods to identify drugs that prevent, treat or halt the progression of a range of conditions in which amyloid fibrils play a part, including Alzheimer's, Parkinson's and Type II diabetes.

The research, also funded by the Wellcome Trust, is published today (August 28 2011) in Nature Chemical Biology.

The team - from Leeds' Astbury Centre for Structural Molecular Biology and Faculty of Biological Sciences - found that an antibiotic known as Rifamycin SV was able to prevent the protein β2microglobulin (β2m) from forming into fibrils. β2m is known to accumulate in renal dialysis patients and forms fibrils within the joints, causing extreme pain and arthritis.

By using a specialised analytical technique called ion mobility spectrometry-mass spectrometry (IMS-MS), the researchers were able to see at what stage of the process Rifamycin SV prevented amyloid fibril formation. They believe the technique could enable potential drugs to be identified for the many other proteins which form amyloid fibrils, linked to a wide range of human disorders.

"Traditional drug design for diseases like Alzheimer's is incredibly difficult because the proteins you're trying to target are changing shape and structure all the time," explains University of Leeds Professor of Structural Molecular Biology, Sheena Radford. "It's like trying to consistently pick out one bead of a particular shape from box of potentially millions of similar beads. This new technique allows us to see the shape of the protein as it changes, so we can more easily identify exactly which part we need to target."

In their normal, folded state, proteins are unable to link together to form long fibrillar assemblies, but if they unfold, they expose areas where they can bind to each other. Initially they form small groups of two, three or four proteins, and then these link into long strands, which twist together to form fibrils.

Most analytical techniques can only show the mass of the protein or its make-up in terms of amino acids, neither of which changes as the protein unfolds. Others are unable to look at individual molecules within complex mixtures. However, IMS-MS can measure the mass and shape of a protein, allowing researchers to watch the unfolding process and the aggregation into small groups and then assembly into the fibril and to find which of these species is able to bind a ligand and stop the assembly process.

In the research published today (28 August 2011), researchers found that Rifamycin SV stopped the formation of protein fibrils by binding to an unfolded protein molecule with a particular shape, enabling for the first time, an unfolded protein of a particular shape to be identified as a target for the design of new inhibitors of fibril assembly.

"We're fortunate to be one of the few universities in the UK able to use IMS-MS to study amyloid fibril formation," says Professor of Biomolecular Mass Spectrometry, Alison Ashcroft, who specialises in this type of analysis. "Although fibrils take years to develop in the body, we are able to 'grow' them in hours in the lab. By using IMS-MS to help us map exactly how they are formed, we can better understand the mechanism by which it happens and - we hope - find ways to stop it."

ENDS

Notes to editors

For more information contact Abigail Chard, Campus PR: tel 0113 357 2105, mobile: 07960 448532 or email abigail@campuspr.co.uk.

The paper: Ligand binding to distinct states diverts aggregation of an amyloid-forming protein is published on August 28 via Advance Online Publication (AOP) on the Nature Chemical Biology website. DOI: 10.1038/NChemBio.635

The papers authors are: Sheena Radford, Alison Ashcroft, Steve Homans, Eric Hewittt, Andrew Hellewell, Geoffrey Platt and Lucy Woods, of the Institute of Molecular and Cellular Biology, Faculty of Biological Sciences at the University of Leeds.

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. For more information visit: www.fbs.leeds.ac.uk.

About University of Leeds

The 2008 Research Assessment Exercise showed the University of Leeds to be the UK's eighth biggest research powerhouse. The University is one of the largest higher education institutions in the UK and a member of the Russell Group of research-intensive universities. The University's vision is to secure a place among the world's top 50 by 2015. For more information visit:  www.leeds.ac.uk.

About BBSRC

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by Government, and with an annual budget of around £445M, we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.

For more information about BBSRC, our science and our impact see: www.bbsrc.ac.uk .
For more information about BBSRC strategically funded institutes see: www.bbsrc.ac.uk/institutes .

External contact

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