Structural Comparison of Mouse and Human α-Synuclein Amyloid Fibrils by Solid-State NMR

JOURNAL OF MOLECULAR BIOLOGY

卷:420

Article

Lv, Guohua¹  Kumar, Ashutosh¹  Giller, Karin¹  Orcellet, Maria L.³  Riedel, Dietmar²  Fernandez, Claudio O.³  Becker, Stefan¹  Lange, Adam¹ 

[1] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany

[2] Max Planck Inst Biophys Chem, Lab Elect Microscopy, D-37077 Gottingen, Germany

[3] Univ Nacl Rosario, Consejo Nacl Invest Cientif & Tecn, Inst Biol Mol & Celular Rosario, RA-2000 Rosario, Argentina

关键词: Parkinson's disease;    magic-angle spinning;    sequential assignment strategy;    secondary structure;    supramolecular arrangement;   

DOI  :  10.1016/j.jmb.2012.04.009

来源: Elsevier

【 摘 要 】

Fibrilar et-synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Mouse AS (mAS) aggregates much faster than human AS (hAS), although mAS differs from hAS at only seven positions in its primary sequence. Currently, little is known about the site-specific structural differences between mAS and hAS fibrils. Here, we applied state-of-the-art solid-state nuclear magnetic resonance (ssNMR) methods to structurally characterize mAS fibrils. The assignment strategy employed a set of high-resolution 2D and 3D ssNMR spectra recorded on uniformly [C-13, N-15], [1-C-13]glucose, and [2-C-13]glucose labeled mAS fibrils. An almost complete resonance assignment (96% of backbone amide N-15 and 93% of all C-13 nuclei) was obtained for residues from Gly41 to Val95, which form the core of mAS fibrils. Six beta-strands were identified to be within the fibril core of mAS based on a secondary chemical shift and NHHC analysis. Intermolecular C-13:N-15 labeled restraints obtained from mixed 1:1 C-13/N-15-labeled mAS fibrils reveal a parallel, in-register supramolecular beta-sheet arrangement. The results were compared in detail to recent structural studies on hAS fibrils and indicate the presence of a structurally conserved motif comprising residues Glu61-Lys80. (C) 2012 Elsevier Ltd. All rights reserved.

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