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Magic Angle Spinning NMR Analysis of β[subscript 2]-Microglobulin Amyloid Fibrils in Two Distinct Morphologies

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dc.contributor.author Debelouchina, Galia Tzvetanova
dc.contributor.author Platt, Geoffrey W.
dc.contributor.author Bayro, Marvin J.
dc.contributor.author Radford, Sheena E.
dc.contributor.author Griffin, Robert Guy
dc.date.accessioned 2012-08-03T14:21:58Z
dc.date.available 2012-08-03T14:21:58Z
dc.date.issued 2010-07
dc.date.submitted 2010-04
dc.identifier.issn 0002-7863
dc.identifier.issn 1520-5126
dc.identifier.uri http://hdl.handle.net/1721.1/71974
dc.description.abstract β[subscript 2]-Microglobulin (β[subscript 2]m) is the major structural component of amyloid fibrils deposited in a condition known as dialysis-related amyloidosis. Despite numerous studies that have elucidated important aspects of the fibril formation process in vitro, and a magic angle spinning (MAS) NMR study of the fibrils formed by a small peptide fragment, structural details of β[subscript 2]m fibrils formed by the full-length 99-residue protein are largely unknown. Here, we present a site-specific MAS NMR analysis of fibrils formed by the full-length β[subscript 2]m protein and compare spectra of fibrils prepared under two different conditions. Specifically, long straight (LS) fibrils are formed at pH 2.5, while a very different morphology denoted as worm-like (WL) fibrils is observed in preparations at pH 3.6. High-resolution MAS NMR spectra have allowed us to obtain [superscript 13]C and [superscript 15]N resonance assignments for 64 residues of β[subscript 2]m in LS fibrils, including part of the highly mobile N-terminus. Approximately 25 residues did not yield observable signals. Chemical shift analysis of the sequentially assigned residues indicates that these fibrils contain an extensive β-sheet core organized in a non-native manner, with a trans-P32 conformation. In contrast, WL fibrils exhibit more extensive dynamics and appear to have a smaller β-sheet core than LS fibrils, although both cores seem to share some common elements. Our results suggest that the distinct macroscopic morphological features observed for the two types of fibrils result from variations in structure and dynamics at the molecular level. en_US
dc.description.sponsorship National Institutes of Health (U.S.) (Grant Number EB003151) en_US
dc.description.sponsorship National Institutes of Health (U.S.) (Grant Number EB002026) en_US
dc.description.sponsorship Wellcome Trust (London, England) (Grant Number 075675) en_US
dc.description.sponsorship Wellcome Trust (London, England) (Grant Number 062164) en_US
dc.language.iso en_US
dc.publisher American Chemical Society (ACS) en_US
dc.relation.isversionof http://dx.doi.org/10.1021/ja102775u en_US
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. en_US
dc.source PMC en_US
dc.title Magic Angle Spinning NMR Analysis of β[subscript 2]-Microglobulin Amyloid Fibrils in Two Distinct Morphologies en_US
dc.type Article en_US
dc.identifier.citation Debelouchina, Galia T. et al. “Magic Angle Spinning NMR Analysis of β[subscript 2]-Microglobulin Amyloid Fibrils in Two Distinct Morphologies.” Journal of the American Chemical Society 132.30 (2010): 10414–10423. en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Chemistry en_US
dc.contributor.department Francis Bitter National Magnet Laboratory en_US
dc.contributor.approver Griffin, Robert Guy
dc.contributor.mitauthor Debelouchina, Galia Tzvetanova
dc.contributor.mitauthor Bayro, Marvin J.
dc.contributor.mitauthor Griffin, Robert Guy
dc.relation.journal Journal of the American Chemical Society en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Author's final manuscript en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Debelouchina, Galia T.; Platt, Geoffrey W.; Bayro, Marvin J.; Radford, Sheena E.; Griffin, Robert G. en


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