6L4S

cryo-em structure of alpha-synuclein fiber mutation type E46K

Summary for 6L4S

• Entry DOI: 10.2210/pdb6l4s/pdb
• EMDB information: 0833
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: alpha-syn fiber, parkinson disease, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 32412.94

Authors

Li, Y.W.,Zhao, K.,Liu, C.,Li, X. (deposition date: 2019-10-21, release date: 2020-04-29, Last modification date: 2024-05-29)

Primary citation

Zhao, K.,Li, Y.,Liu, Z.,Long, H.,Zhao, C.,Luo, F.,Sun, Y.,Tao, Y.,Su, X.D.,Li, D.,Li, X.,Liu, C.
Parkinson's disease associated mutation E46K of alpha-synuclein triggers the formation of a distinct fibril structure.
Nat Commun, 11:2643-2643, 2020

PubMed 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.

PubMed: 32457390
DOI: 10.1038/s41467-020-16386-3

Experimental method

ELECTRON MICROSCOPY (3.37 Å)