6L1T

Cryo-EM structure of phosphorylated Tyr39 a-synuclein amyloid fibril

Summary for 6L1T

• Entry DOI: 10.2210/pdb6l1t/pdb
• EMDB information: 0801
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: amyloid fibril, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 10
• Total formula weight: 145560.87

Authors

Liu, C.,Li, Y.M.,Zhao, K.,Lim, Y.J.,Liu, Z.Y. (deposition date: 2019-09-30, release date: 2020-08-12, Last modification date: 2024-10-23)

Primary citation

Zhao, K.,Lim, Y.J.,Liu, Z.,Long, H.,Sun, Y.,Hu, J.J.,Zhao, C.,Tao, Y.,Zhang, X.,Li, D.,Li, Y.M.,Liu, C.
Parkinson's disease-related phosphorylation at Tyr39 rearranges alpha-synuclein amyloid fibril structure revealed by cryo-EM.
Proc.Natl.Acad.Sci.USA, 117:20305-20315, 2020

PubMed Abstract: 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-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 α-syn fibril, which reveals a fold of α-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 α-syn. This structure composed of residues 1 to 100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 α-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.

PubMed: 32737160
DOI: 10.1073/pnas.1922741117

Experimental method

ELECTRON MICROSCOPY (3.22 Å)