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Intermolecular Alignment in Beta 2-Microglobulin Amyloid Fibrils

Author(s)
Debelouchina, Galia Tzvetanova; Bayro, Marvin J.; Radford, Sheena E.; Griffin, Robert Guy; Platt, Geoffrey W.
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Abstract
The deposition of amyloid-like fibrils, composed primarily of the 99-residue protein β2-microglobulin (β2m), is one of the characteristic symptoms of dialysis-related amyloidosis. Fibrils formed in vitro at low pH and low salt concentration share many properties with the disease related fibrils and have been extensively studied by a number of biochemical and biophysical methods. These fibrils contain a significant β-sheet core and have a complex cryoEM electron density profile. Here, we investigate the intrasheet arrangement of the fibrils by means of [superscript 15]N−[superscript 13]C MAS NMR correlation spectroscopy. We utilize a fibril sample grown from a 50:50 mixture of [superscript 15]N,[superscript 12]C- and [superscript 14]N,[superscript 13]C-labeled β2m monomers, the latter prepared using 2-[superscript 13]C glycerol as the carbon source. Together with the use of ZF-TEDOR mixing, this sample allowed us to observe intermolecular [superscript 15]N−[superscript 13]C backbone-to-backbone contacts with excellent resolution and good sensitivity. The results are consistent with a parallel, in-register arrangement of the protein subunits in the fibrils and suggest that a significant structural reorganization occurs from the native to the fibril state.
Date issued
2010-11
URI
http://hdl.handle.net/1721.1/72019
Department
Massachusetts Institute of Technology. Department of Chemistry; Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology)
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Debelouchina, Galia T. et al. “Intermolecular Alignment in β2-Microglobulin Amyloid Fibrils.” Journal of the American Chemical Society 132.48 (2010): 17077–17079. Copyright 2010 American Chemical Society.
Version: Final published version
ISSN
0002-7863
1520-5126

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