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Parkinson's disease-related phosphorylation at Tyr39 rearranges ?-synuclein amyloid fibril structure revealed by cryo-EM.


ABSTRACT: Posttranslational modifications (PTMs) of ?-synuclein (?-syn), e.g., phosphorylation, play an important role in modulating ?-syn pathology in Parkinson's disease (PD) and ?-synucleinopathies. Accumulation of phosphorylated ?-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to ?-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous ?-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-electron microscopy (cryo-EM) structure of the pY39 ?-syn fibril, which reveals a fold of ?-syn with pY39 in the center of the fibril core forming an electrostatic interaction network with eight charged residues in the N-terminal region of ?-syn. This structure composed of residues 1 to 100 represents the largest ?-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 ?-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

SUBMITTER: Zhao K 

PROVIDER: S-EPMC7443891 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Parkinson's disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM.

Zhao Kun K   Lim Yeh-Jun YJ   Liu Zhenying Z   Long Houfang H   Sun Yunpeng Y   Hu Jin-Jian JJ   Zhao Chunyu C   Tao Youqi Y   Zhang Xing X   Li Dan D   Li Yan-Mei YM   Liu Cong C  

Proceedings of the National Academy of Sciences of the United States of America 20200731 33


Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson's disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site  ...[more]

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