RT Journal Article
SR Electronic
T1 Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 870758
DO 10.1101/870758
A1 Zhao, Kun
A1 Li, Yaowang
A1 Liu, Zhenying
A1 Long, Houfang
A1 Zhao, Chunyu
A1 Luo, Feng
A1 Sun, Yunpeng
A1 Tao, Youqi
A1 Su, Xiao-dong
A1 Li, Dan
A1 Li, Xueming
A1 Liu, Cong
YR 2019
UL http://biorxiv.org/content/early/2019/12/11/870758.abstract
AB α-Synuclein (α-syn) amyloid fibril, as the major component of Lewy bodies and pathological entity spreading in human brain, 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 determined the cryo-EM structure of a full-length α-syn fibril formed by N-terminal acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a new 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 a higher capability of seeding fibril formation 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.