By pin-pointing the reaction that kick-starts the formation of amyloid fibres, scientists can now seek to further understand how these fibrils develop and cause disease.
Amyloid fibres, which are implicated in a wide range of diseases, form when proteins misfold and stick together in long, rope-like structures. Until now the nature of the first misfold, which then causes a chain reaction of misfolding by other proteins, was unknown.
Funded by the University of Leeds and The Wellcome Trust, the research published in Molecular Cell today is the culmination of four years of work led by Sheena Radford, Professor of Structural Molecular Biology and Deputy Director of the Astbury Centre for Structural Molecular Biology at the University of Leeds.
She explains: "We wanted to discover what happened to make a perfectly normal protein into one which was prone to aggregation because if we can stop the very first event, which causes a snowball effect, it provides us with new targets for future therapies."
The team first had to make a protein called beta-2 micro globulin, which when folded in a particular way is known to have a major role to play in the formation of amyloid fibres. These fibres particularly affect patients with kidney disease where they create deposits that can accumulate in the joints.
"Working kidneys get rid of beta-2 microglobulin," says Professor Radford. "But if you don't have properly functioning kidneys, you get a build up of the protein which can result in dialysis-related amyloidosis, which can be very painful."
The researchers went on to solve the structure of this misfolded variant of beta-2 micro globulin - the first time its structure in its dangerous form has been directly shown. This allowed them to witness the properties that encourage other proteins to misfold and become amyloidegenic too.
Using nuclear magnetic resonance spectroscopy (NMR) to obtain high definition 3D images to view the structures, they found that only a small change or misfold in the protein made it unstable, causing it to become highly excitable and dynamic. This made it more likely to stick to other proteins, influencing their structure and starting off the snowball effect of aggregation.
"We saw that the variant protein bumped into others, stuck to them and changed their structure so that they too were amyloidegenic," says Professor Radford. "This is a huge step forward, not just for renal patients, but in our fundamental understanding of how amyloid fibres may form in other diseases as well. Many amyloid diseases are due to changes in protein structure and our next steps will be to see if similar changes are taking place with other protein types."
Helen Miller, Innovate UK (Apr 2018), £999,960
Elisabetta Groppelli, David Rowlands & Stanley Lemon (University of North Carolina), Medical Research Foundation Fellowship (Apr 2018), £293,494
Nikesh Patel, Medical Research Foundation fellowship (Apr 2018), £290,976
Jessica Kwok & Ralf Richter, Leverhulme Trust (Apr 2018), £298,273
Julie Aspden, Royal Society (Apr 2018), £20,000
Liz Duncan, Royal Society (Mar 2018), £14,602
Alex O'Neill & Ryan Seipke, BBSRC (Feb 2018), £45,489
Jim Deuchars, Royal Society (Feb 2018), £16,300
Stefan Kepinski & Netta Cohen, Leverhulme Trust (Feb 2018), £320,387
Lisa Collins, BBSRC (Feb 2018), £49,950
Lars Jeuken, BBSRC (Feb 2018), £30,000
Nikita Gamper, BBSRC (Feb 2018), £30,000
Alison Baker, BBSRC (Feb 2018), £30,000
Scott Bowen, Leducq Foundation Grant (Feb 2018), £28,470
Jessica Kwok and Ronaldo Ichiyama, International Spinal Research Trust (Feb 2018), £94,450
Alex O'Neill, Oxford Drug Design (Jan 2018), £86,098
Dave Lewis and Colleagues in South Africa, HEFCE Global Challenge Research (Jan 2018), £48,000
Sarah Calaghan, Ed White, John Colyer, Isuru Jayasinghe, BHF (Jan 2018), £128,308
Christine Foyer and Alison Baker, HEFCE GCRF Grant (Jan 2018), £71,158
Alison Baker, Yun Yung Gong and Lindsay Stringer and ICRISAT India, HEFCE GCRF Grant (Jan 2018), £27,000
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Alison Dunn, NERC (Dec 2017), £18,000
Jennifer Tomlinson, Royal Society-Research Fellows Enhancement Award (Dec 2017), £94,681
Helen Miller, AB AGri Grant (Dec 2017), £73,600
Simon Walker, Royal Society Enhancement Award (Dec 2017), £10,000
Carrie Ferguson, Bryan Taylor, Harry Rossiter, The Physiological Society (Dec 2017), £7,392
Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
Neil Ranson, Darren Tomlinson, BBSRC (Oct 2017), £494,318
Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
Neil Ranson, Juan Fontana, Mark Harris, Michelle Peckham, Ralf Richter, Peter Stockley, Patricija Van Oosten-Hawle and colleagues in Engineering, FMH and MAPS, Wellcome Trust Equipment Call (Sep 2017), £418,000
Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000
Ralf Richter, David Brockwell, Eric Hewitt, Jessica Kwok, Emanuele Paci and MAPS/FMH, BBSRC (Jun 2017), £600,000
Eric Blair, Adrian Whitehouse, Nicola Stonehouse, Alison Baker, Richard Bayliss, Joan Boyes, Ryan Seipke, Sally Boxall and MAPS/FMH, BBSRC (Jun 2017), £376,000
Stefan Kepinski, Yoselin Benitez-Alfonso, Tom Bennett, Michelle Peckham, BBSRC (Jun 2017), £331,000
Roman Tuma, Lars Jeuken, Paul Millner, Sheena Radford, Peter Stockley and MAPS/FMH, BBSRC (Jun 2017), £222,000
Vas Ponnambalam, Darren Tomlinson, Stephen Wheatcroft, BHF (May 2017), £107,878