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- Title
Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure.
- Authors
Zhao, Kun; Li, Yaowang; Liu, Zhenying; Long, Houfang; Zhao, Chunyu; Luo, Feng; Sun, Yunpeng; Tao, Youqi; Su, Xiao-dong; Li, Dan; Li, Xueming; Liu, Cong
- Abstract
Amyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson's disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs. The E46K α-synuclein mutation causes familial Parkinson's disease. Here, the authors present the cryo-EM structure of N-terminally acetylated E46K α-synuclein fibrils and find that it is distinct from other known α-synuclein fibril structures.
- Subjects
PARKINSON'S disease; AMYLOID beta-protein; PRESENILINS; ELECTROSTATIC interaction
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-16386-3