NMR helps unravel amyloid story

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  • Published: Dec 1, 2004
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: NMR helps unravel amyloid story

The self-assembling filamentous strands of protein known as amyloid fibrils are at the root Alzheimer's disease and the spongiform encephalopathies, such as CJD. Now, an Anglo American team has used magic angle spinning NMR to reveal the high-resolution molecular structure of a peptide in such an amyloid fibril. The results could ultimately help improve our understanding of whether amyloid fibrils and the plaques they form are a cause or an effect of these diseases as well as perhaps suggesting new therapeutic approaches.

To date, no atomic-resolution structures of amyloid fibrils have been obtained. There is a simple reason for this - by their very nature they are insoluble and it has proved impossible to prepare diffraction-quality samples for crystallographers. Where diffraction techniques fail proteins, however, NMR can often step into the fold.

Christopher Jaroniec, Cait MacPhee, Vikram Bajaj, Michael McMahon, Christopher Dobson, and Robert Griffin of the Department of Chemistry and Center for Magnetic Resonance, at the Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, USA and the Cavendish Laboratory at the University of Cambridge, UK, have reported such a high-resolution structure using MAS NMR. The analysis was carried out on a peptide fragment of the amyloidogenic protein transthyretin, TTR(105-115), in its fibrillar form.

The researchers were able not only to reveal the backbone fold of the peptide but also the precise conformation of the side chains. Two important characteristic of the fibrils that have evaded others at this resolution. Their findings go part of the way to explain why these polypeptide assemblies have such unusual stability, which could suggest a new rationale for their formation and persistence in the diseased brain.

"This study represents the initial required step before examining the larger proteins associated with disease," Griffin told Resonants, "If you cannot do the structure of an 11-mer amyloid peptide, then there is little chance that of studying larger systems." The researchers have shown that the solid-state NMR methods are suitable for this type of structure determination and at the same time MacPhee's studies reveal the fibrils to be ordered at the microscopic scale. "The bottom line is that this study sets the stage for structural investigations of larger proteins associated with disease," he adds.

Amyloid fibrils
Amyloid fibrils

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