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Intermolecular alignment in Y145Stop human prion protein amyloid fibrils probed by solid-state NMR spectroscopy.


ABSTRACT: The Y145Stop mutant of human prion protein, huPrP23-144, has been linked to PrP cerebral amyloid angiopathy, an inherited amyloid disease, and also serves as a valuable in vitro model for investigating the molecular basis of amyloid strains. Prior studies of huPrP23-144 amyloid by magic-angle-spinning (MAS) solid-state NMR spectroscopy revealed a compact ?-rich amyloid core region near the C-terminus and an unstructured N-terminal domain. Here, with the focus on understanding the higher-order architecture of huPrP23-144 fibrils, we probed the intermolecular alignment of ?-strands within the amyloid core using MAS NMR techniques and fibrils formed from equimolar mixtures of (15)N-labeled protein and (13)C-huPrP23-144 prepared with [1,3-(13)C(2)] or [2-(13)C]glycerol. Numerous intermolecular correlations involving backbone atoms observed in 2D (15)N-(13)C spectra unequivocally suggest an overall parallel in-register alignment of the ?-sheet core. Additional experiments that report on intermolecular (15)N-(13)CO and (15)N-(13)C? dipolar couplings yielded an estimated strand spacing that is within ?10% of the distances of 4.7-4.8 Å typical for parallel ?-sheets.

SUBMITTER: Helmus JJ 

PROVIDER: S-EPMC3164902 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Intermolecular alignment in Y145Stop human prion protein amyloid fibrils probed by solid-state NMR spectroscopy.

Helmus Jonathan J JJ   Surewicz Krystyna K   Apostol Marcin I MI   Surewicz Witold K WK   Jaroniec Christopher P CP  

Journal of the American Chemical Society 20110815 35


The Y145Stop mutant of human prion protein, huPrP23-144, has been linked to PrP cerebral amyloid angiopathy, an inherited amyloid disease, and also serves as a valuable in vitro model for investigating the molecular basis of amyloid strains. Prior studies of huPrP23-144 amyloid by magic-angle-spinning (MAS) solid-state NMR spectroscopy revealed a compact β-rich amyloid core region near the C-terminus and an unstructured N-terminal domain. Here, with the focus on understanding the higher-order ar  ...[more]

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