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Cryo-EM structure of phosphorylated Tyr39 a-synuclein amyloid fibrilCryo-EM structure of phosphorylated Tyr39 a-synuclein amyloid fibril
Structural highlights
Publication Abstract from PubMedPosttranslational modifications (PTMs) of alpha-synuclein (alpha-syn), e.g., phosphorylation, play an important role in modulating alpha-syn pathology in Parkinson's disease (PD) and alpha-synucleinopathies. Accumulation of phosphorylated alpha-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to alpha-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous alpha-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 alpha-syn fibril, which reveals a fold of alpha-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 alpha-syn. This structure composed of residues 1 to 100 represents the largest alpha-syn fibril core determined so far. This work provides structural understanding on the pathology of the pY39 alpha-syn fibril and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases. Parkinson's disease-related phosphorylation at Tyr39 rearranges alpha-synuclein amyloid fibril structure revealed by cryo-EM.,Zhao K, Lim YJ, Liu Z, Long H, Sun Y, Hu JJ, Zhao C, Tao Y, Zhang X, Li D, Li YM, Liu C Proc Natl Acad Sci U S A. 2020 Jul 31. pii: 1922741117. doi:, 10.1073/pnas.1922741117. PMID:32737160[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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