Unique Identification of Supramolecular Structures in Amyloid Fibrils by Solid-State NMR Spectroscopy
Unique Identification of Supramolecular Structures in Amyloid Fibrils by Solid-State NMR Spectroscopy
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DOI：
10.1002/anie.200804198
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Nielsen, Niels C.
中科院分区：
文献类型：
--
作者：
Nielsen, Jakob T.;Bjerring, Morten;Nielsen, Niels C.
In recent years, considerable progress has been made in using solid-state NMR spectroscopy to determine atomic-resolution structures of amyloid fibrils [1–4] associated with serious disorders such as Alzheimer s and Parkinson s diseases, prion diseases, and type 2 diabetes. Although the architecture of fibrils is considered to be a continuous stack of b-sheet ladders, termed a cross-b structure,[5] there may be significant variations in the supramolecular organization of the peptides within the fibrils. Detailed insight may shed light on the assembly process and inspire design of fibril-binding compounds and inhibitors.Like its liquid-state analogue, solid-state NMR spectroscopy is based on local structure information and does not automatically provide long-range structure-symmetry information as known from X-ray crystallography. As a consequence, large amounts of data on several differently labeled samples have typically been required to obtain sufficient longrange information. Herein, we demonstrate that it is possible to identify the supramolecular conformation of fibrils directly from symmetry-induced resonance patterns in 2D solid-state NMR spectra for a single 13C, 15N-labeled sample. Our target is the hIAPP20–29 (SNNFGAILSS) decapeptide from the human islet amyloid polypeptide (hIAPP), which is believed to form the fibrillation core domain of fibrils in the pancreas of type 2 diabetes patients.[6, 7] To appreciate the NMR signatures of fibril symmetry, it is necessary to understand the structural determinants of fibrils. Fibrils are formed by peptides in extended conformations (b strands) into ladders (Figure1a, top) through parallel or antiparallel bridges (hydrogen bonds), which through steric effects further combine into stacked ladders, called a zipper [8](Figure 1a, bottom). The stacking of the two ladders may occur with different orientation of the strands defining, in total, eight classes of steric zippers [8] with different numbers of nonequivalent copies of the peptides, as illustrated for the NFGAILS fragment of hIAPP (Figure 1 b). Such zippers can, in combination with a few long-range constraints, be uniquely distinguished using solid-state NMR spectroscopy since structurally nonequivalent peptides give rise to distinct resonance sets.
