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."
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
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
Graham Askew in collaboration with Bangor University, BBSRC (Mar 2017), £477,383
Stephen Muench, BBSRC (Mar 2017), £132,945
Nic Stonehouse, MRC (Mar 2017), £906,341
Bill Kunin, Steve Sait, BBSRC (Mar 2017), £602,831
Adrian Goldman, EU (Mar 2017), £546,576
Sheena Radford, Wellcome Trust (Mar 2017), £1,836,482
Jamie Johnston, Royal Society (Mar 2017), £15,000
Beatrice Filippi, Royal Society (Mar 2017), £15,000
Tom Bennett, Royal Society (Mar 2017), £15,000
Ryan Seipke, BBSRC (Feb 2017), £52,116
Mary O'Connell, BBSRC (Feb 2017), £46,986
Hannah Dugdale, NERC (Feb 2017), £504,138
Anastasia Zhuravleva, EPSRC (Jan 2017), £100,792
Richard Bayliss, Cancer Research UK (Jan 2017), £1,600,000
John Barr, EU (Jan 2017), £339,000
Mark Harris, Royal Society (Jan 2017), £250,000
Alison Dunn, NERC (Jan 2017), £105,000
Alex Breeze, Pancreatic Cancer Research Fund (Jan 2017), £180,000
Alison Dunn, NERC (Dec 2016), £18,000
Lisa Collins, BBSRC (Dec 2016), £1,681,835
Brendan Davies, Leverhulme Trust (Dec 2016), £247,555
Alan Benson, Mark Drinkhill, Ed White, British Heart Foundaion (Dec 2016), £217,223
Adrian Goldman, Royal Society (Dec 2016), £82,999
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, RCUK (Nov 2016), £484,172
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, Wellcome Trust (Nov 2016), £119,343
Katie Field, Rank Prize Funds (Nov 2016), £20,000
Jessica Kwok, Royal Society (Nov 2016), £14,948
John Ladbury, Cancer Research UK (Oct 2016), £4,250
Miriam Wittmann, Martin Stacey, Edward Vital, Lupus UK
(Oct 2016), £34,010
Valerie Speirs, NC3Rs
(Oct 2016), £90,000
Nicola Stonehouse, Morgan Herod, David Rowlands, BBSRC
(Sep 2016), £436,424
Joseph Cockburn, Wellcome Trust
(Sep 2016), £100,000
John Barr, Public Health England
(Sep 2016), £94,471
Helen Miller, DSM Nutritional Products A/S
(Sep 2016), £54,680
Steven Clapcote, Vitaflo International Ltd
(Sep 2016), £39,285
Juan Fontana Jordan De Urries
, Royal Society
(Sep 2016), £21,793
Jing Li, Sarah Calaghan, Mark Drinkhill, British Heart Foundation
(Sep 2016), £117,585