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

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• 作者：Marc A. Caporini ; Vikram S. Bajaj ; Mikhail Veshtort ; Anthony Fitzpatrick ; Cait E. MacPhee ; Michele Vendruscolo ; Christopher M. Dobson ; Robert G. Griffin
• 刊名：Journal of Physical Chemistry B
• 出版年：2010
• 出版时间：October 28, 2010
• 年：2010
• 卷：114
• 期：42
• 页码：13555-13561
• 全文大小：343K
• 年卷期：v.114,no.42(October 28, 2010)
• ISSN：1520-5207

文摘

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 (TTR_105−115), we introduce single 1-¹³C labeled amino acids at seven different sites in the peptide and measure intermolecular carbonyl−carbonyl distances with an accuracy of 0.11 A. Our results conclusively establish a parallel, in register, topology for the packing of this peptide into a β-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.