New technique reveals secrets of amyloid
12 Oct 2011 by Evoluted New Media
Amyloid fibrils are characteristic of diseases like Alzheimer’s, Parkinson’s and type 2 diabetes, but how they form is unclear – now researchers are using a special analytical technique to establish how fibrils form.
The technique – ion mobility spectrometry-mass spectrometry (IMS-MS) – has enabled scientists for the first time to identify drugs to prevent, treat or halt the progression of conditions involving amyloid fibrils.
Unlike most techniques which only look at the mass of proteins or its make-up in terms of amino acids, IMS-MS allows scientists to measure the mass and shape of a protein, and watch its unfolding process. It also means they can study amyloid formation, and identify what might stop the assembly process.
Researchers from the University of Leeds’ Astbury Centre for Structural Molecular Biology and faculty of biological sciences used the technique to resolve the intermediates of amyloid assembly. Their work – published in nature Chemical Biology – found that the antibiotic rifamycin SV was able to prevent the protein ß2microglobulin (ß2m) from forming fibrils.
“We’re fortunate to be one of the few universities in the UK able to use IMS-MS to study amyloid fibril formation,” said Alison Ashcroft, professor of biomolecular mass spectrometry. “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.”
In their normal, folded state, proteins are unable to link together to form fibrils, but as they unfold, they expose areas which can bind together, forming small groups of two or three. These then link into longer strands and twist together to form fibrils.
Researchers found that rifamycin SV prevents protein fibril formation by binding to an unfolded protein molecule with a particular shape, which can be used as a target for inhibitors of fibril assembly. It inhibits ß2m fibrillation by binding distinct monomeric conformers, disfavouring oligomer formation and diverting the course of assembly to the formation of spherical aggregates.
Ligand binding to distinct states diverts aggregation of amyloid-forming protein.
