Structural Insights into α-Synuclein Fibril Polymorphism: Effects of Parkinson's Disease-Related C-Terminal Truncations

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Ni, Xiaodan¹  McGlinchey, Ryan P.²  Jiang, Jiansen¹  Lee, Jennifer C.² 

[1] NHLBI, Lab Membrane Prot & Struct Biol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA

[2] NHLBI, Lab Prot Conformat & Dynam, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA

关键词: cryoEM;    TEM;    thioflavin T;    amyloid;    Raman spectroscopy;   

DOI  :  10.1016/j.jmb.2019.07.001

来源: Elsevier

【 摘 要 】

Lewy bodies, hallmarks of Parkinson's disease, contain C-terminally truncated (Delta C) alpha-synuclein (alpha-syn). Here, we report fibril structures of three N-terminally acetylated (Ac) alpha-syn constructs, Ac1-140, Ac1-122, and Ac1-103, solved by cryoelectron microscopy. Both Delta C-alpha-syn variants exhibited faster aggregation kinetics, and Ac1-103 fibrils efficiently seeded the full-length protein, highlighting their importance in pathogenesis. Interestingly, fibril helical twists increased upon the removal of C-terminal residues and can be propagated through cross-seeding. Compared to that of Ac1-140, increased electron densities were seen in the N-terminus of Ac1-103, whereas the C-terminus of Ac1-122 appeared more structured. In accord, the respective termini of Delta C-alpha-syn exhibited increased protease resistance. Despite similar amyloid core residues, distinctive features were seen for both Ac1-122 and Ac1-103. Particularly, Ac1-103 has the tightest packed core with an additional turn, likely attributable to conformational changes in the N-terminal region. These molecular differences offer insights into the effect of C-terminal truncations on alpha-syn fibril polymorphism. Published by Elsevier Ltd.

【 授权许可】

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