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High Resolution Structural Characterization of A beta(42) Amyloid Fibrils by Magic Angle Spinning NMR

Covin, Michael T.; Silvers, Robert; Frohm, Birgitta LU ; Su, Yongchao; Linse, Sara LU and Griffin, Robert G. (2015) In Journal of the American Chemical Society 137(23). p.7509-7518
Abstract
The presence of amyloid plaques composed of amyloid beta (A beta) fibrils is a hallmark of Alzheimer's disease (AD). The A beta peptide is present as several length variants with two common alloforms consisting of 40 and 42 amino acids, denoted A beta(1-40) and A beta(1-42), respectively. While there have been numerous reports that structurally characterize fibrils of A beta(1-40), very little is known about the structure of amyloid fibrils of A beta(1-42), which are considered the more toxic alloform involved in AD. We have prepared isotopically C-13/N-13 labeled A beta(M01-42) fibrils in vitro from recombinant protein and examined their C-13-C-13 and C-13-N-15 magic angle spinning (MAS) NMR spectra. In contrast to several other studies... (More)
The presence of amyloid plaques composed of amyloid beta (A beta) fibrils is a hallmark of Alzheimer's disease (AD). The A beta peptide is present as several length variants with two common alloforms consisting of 40 and 42 amino acids, denoted A beta(1-40) and A beta(1-42), respectively. While there have been numerous reports that structurally characterize fibrils of A beta(1-40), very little is known about the structure of amyloid fibrils of A beta(1-42), which are considered the more toxic alloform involved in AD. We have prepared isotopically C-13/N-13 labeled A beta(M01-42) fibrils in vitro from recombinant protein and examined their C-13-C-13 and C-13-N-15 magic angle spinning (MAS) NMR spectra. In contrast to several other studies of A beta fibrils, we observe spectra with excellent resolution and a single set of chemical shifts, suggesting the presence of a single fibril morphology. We report the initial structural characterization of A beta(M01-42) fibrils utilizing C-13 and N-15 shift assignments of 38 of the 43 residues, including the backbone and side chains, obtained through a series of cross-polarization based 2D and 3D C-13-C-13, C-13-N-15 MAS NMR experiments for rigid residues along with J-based 2D TOBSY experiments for dynamic residues. We find that the first similar to 5 residues are dynamic and most efficiently detected in a J-based TOBSY spectrum. In contrast, residues 16-42 are easily observed in cross-polarization experiments and most likely form the amyloid core. Calculation of psi and phi dihedral angles from the chemical shift assignments indicate that beta-strands are present in the fibril's secondary structure. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of the American Chemical Society
volume
137
issue
23
pages
7509 - 7518
publisher
The American Chemical Society
external identifiers
  • wos:000356753700039
  • scopus:84935005034
ISSN
1520-5126
DOI
10.1021/jacs.5b03997
language
English
LU publication?
yes
id
dcc71a2b-365c-46bd-80f1-fc547c36a11b (old id 7590622)
date added to LUP
2015-07-23 08:32:32
date last changed
2017-11-12 03:48:22
@article{dcc71a2b-365c-46bd-80f1-fc547c36a11b,
  abstract     = {The presence of amyloid plaques composed of amyloid beta (A beta) fibrils is a hallmark of Alzheimer's disease (AD). The A beta peptide is present as several length variants with two common alloforms consisting of 40 and 42 amino acids, denoted A beta(1-40) and A beta(1-42), respectively. While there have been numerous reports that structurally characterize fibrils of A beta(1-40), very little is known about the structure of amyloid fibrils of A beta(1-42), which are considered the more toxic alloform involved in AD. We have prepared isotopically C-13/N-13 labeled A beta(M01-42) fibrils in vitro from recombinant protein and examined their C-13-C-13 and C-13-N-15 magic angle spinning (MAS) NMR spectra. In contrast to several other studies of A beta fibrils, we observe spectra with excellent resolution and a single set of chemical shifts, suggesting the presence of a single fibril morphology. We report the initial structural characterization of A beta(M01-42) fibrils utilizing C-13 and N-15 shift assignments of 38 of the 43 residues, including the backbone and side chains, obtained through a series of cross-polarization based 2D and 3D C-13-C-13, C-13-N-15 MAS NMR experiments for rigid residues along with J-based 2D TOBSY experiments for dynamic residues. We find that the first similar to 5 residues are dynamic and most efficiently detected in a J-based TOBSY spectrum. In contrast, residues 16-42 are easily observed in cross-polarization experiments and most likely form the amyloid core. Calculation of psi and phi dihedral angles from the chemical shift assignments indicate that beta-strands are present in the fibril's secondary structure.},
  author       = {Covin, Michael T. and Silvers, Robert and Frohm, Birgitta and Su, Yongchao and Linse, Sara and Griffin, Robert G.},
  issn         = {1520-5126},
  language     = {eng},
  number       = {23},
  pages        = {7509--7518},
  publisher    = {The American Chemical Society},
  series       = {Journal of the American Chemical Society},
  title        = {High Resolution Structural Characterization of A beta(42) Amyloid Fibrils by Magic Angle Spinning NMR},
  url          = {http://dx.doi.org/10.1021/jacs.5b03997},
  volume       = {137},
  year         = {2015},
}