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

Jonathan J Helmus1, Krystyna Surewicz, Marcin I Apostol

  • 1Department of Chemistry, The Ohio State University, Columbus, 43210, United States.

Journal of the American Chemical Society
|August 11, 2011
PubMed

Insights

The Y145Stop mutant of human prion protein forms amyloid fibrils with a parallel in-register beta-sheet core. This finding advances understanding of prion protein amyloid structure and disease mechanisms.

Area of Science:

  • Structural Biology
  • Neurodegenerative Diseases
  • Biophysics

Background:

  • The Y145Stop mutant of human prion protein (huPrP23-144) is implicated in PrP cerebral amyloid angiopathy.
  • This mutant serves as a model for studying amyloid strains and their molecular basis.
  • Previous studies identified a compact, beta-rich core and an unstructured N-terminus in huPrP23-144 amyloid fibrils.

Purpose of the Study:

  • To investigate the higher-order architecture of huPrP23-144 amyloid fibrils.
  • To determine the intermolecular alignment of beta-strands within the amyloid core.

Main Methods:

  • Magic-angle-spinning (MAS) solid-state NMR spectroscopy was employed.
  • Fibrils were prepared from equimolar mixtures of isotopically labeled proteins ((15)N and (13)C).
  • Intermolecular correlations and dipolar couplings were analyzed.

Main Results:

  • Numerous intermolecular correlations in 2D (15)N-(13)C spectra indicated parallel in-register alignment of beta-sheets.
  • Intermolecular (15)N-(13)CO and (15)N-(13)Cα dipolar couplings provided strand spacing estimates.
  • The estimated strand spacing was approximately 4.7-4.8 Å, consistent with parallel beta-sheets.

Conclusions:

  • The study unequivocally suggests a parallel in-register alignment of beta-strands in the huPrP23-144 amyloid core.
  • This structural insight is crucial for understanding prion protein amyloid formation and associated diseases.

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