Department of Biochemistry, Weill Cornell Medical College, New York, New York; Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany.
Department of Biosciences and Bioengineering, Indian Institute of Technology, Mumbai, India; Department of NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany.
Biophys J. 2018 Jun 19;114(12):2811-2819. doi: 10.1016/j.bpj.2018.05.011.
Fibrillar α-synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Using solid-state nuclear magnetic resonance (ssNMR), we previously reported a structural characterization of mouse AS (mAS) fibrils and found that the secondary structure of the mAS fibrils is highly similar to a form of human AS (hAS) fibrils. Recently, a three-dimensional structure of these same hAS fibrils was determined by ssNMR and scanning transmission electron microscopy. Using medium- and long-range distance restraints obtained from ssNMR spectra, we found that the single protofilament structure of mAS fibrils is also similar to that of the hAS fibrils. However, residue-specific water accessibility of mAS fibrils probed by water polarization transfer ssNMR measurements indicates that residues S42-T44 and G84-V95 are largely protected from water even though they are located at the edge of the protofilament. Some of the corresponding resonances also exhibit peak doubling. These observations suggest that these residues may be involved in, to our knowledge, a novel protofilament-protofilament interface. We propose a structural model of mAS fibrils that incorporates this dimer interface.
纤维状的α-突触核蛋白（AS）是路易体的主要成分，是帕金森病的病理标志。我们之前使用固态核磁共振（ssNMR）对小鼠 AS（mAS）纤维进行了结构特征描述，并发现 mAS 纤维的二级结构与人类 AS（hAS）纤维的一种形式高度相似。最近，通过 ssNMR 和扫描透射电子显微镜确定了这些相同的 hAS 纤维的三维结构。使用从中获得的中程和长程距离约束ssNMR 光谱，我们发现 mAS 纤维的单原纤维结构也与 hAS 纤维相似。然而，通过水极化转移 ssNMR 测量探测到 mAS 纤维的残基特异性水可及性表明，尽管这些残基位于原纤维的边缘，但 S42-T44 和 G84-V95 残基仍基本不受水的影响。一些相应的共振也表现出峰加倍。这些观察结果表明，这些残基可能参与了一种我们所知的新型原纤维-原纤维界面。我们提出了一种包含这种二聚体界面的 mAS 纤维结构模型。
