Accurate Determination of Interstrand Distances and Alignment in Amyloid Fibrils by Magic Angle Spinning NMR

Marc A. Caporini, Vikram S. Bajaj, Mikhail Veshtort, Anthony Fitzpatrick, Cait E. MacPhee, Michele Vendruscolo, Christopher M. Dobson, Robert G. Griffin

Research output: Contribution to journalArticlepeer-review

Abstract

Amyloid fibrils are structurally ordered aggregates of proteins whose formation is associated with many neurodegenerative and other diseases. For that reason, their high-resolution structures are of considerable interest and have been studied using a wide range of techniques, notably electron microscopy, X-ray diffraction, and magic angle spinning (MAS) NMR. Because of the excellent resolution in the spectra, MAS NMR is uniquely capable of delivering site-specific, atomic resolution information about all levels of amyloid structure: (1) the monomer, which packs into several (2) protofilaments that in turn associate to form a (3) fibril. Building upon our high-resolution structure of the monomer of an amyloid-forming peptide from transthyretin (TTR105-115), we introduce single 1-C-13 labeled amino acids at seven different sites in the peptide and measure intermolecular carbonyl-carbonyl distances with an accuracy of similar to 0.11 A. Our results conclusively establish a parallel, in register, topology for the packing of this peptide into a beta-sheet and provide constraints essential for the determination of an atomic resolution structure of the fibril. Furthermore, the approach we employ, based on a combination of a double-quantum filtered variant of the DRAWS recoupling sequence and multispin numerical simulations in SPINEVOLUTION, is general and should be applicable to a wide range of systems.

Original languageEnglish
Pages (from-to)13555-13561
Number of pages7
JournalJournal of Physical Chemistry B (Soft Condensed Matter and Biophysical Chemistry)
Volume114
Issue number42
DOIs
Publication statusPublished - 28 Oct 2010

Keywords

  • SOLID-STATE NMR
  • NUCLEAR-MAGNETIC-RESONANCE
  • ECHO DOUBLE-RESONANCE
  • ROTATING SOLIDS
  • CORRELATION SPECTROSCOPY
  • STAPHYLOCOCCUS-AUREUS
  • QUANTUM RELAXATION
  • STRUCTURAL MODEL
  • TORSIONAL ANGLE
  • PULSE SEQUENCES

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