Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure
| Autor: | Houfang Long, Cong Liu, Dan Li, Yunpeng Sun, Chunyu Zhao, Xueming Li, Yaowang Li, Feng Luo, Kun Zhao, Youqi Tao, Xiao-Dong Su, Zhenying Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Amyloid Protein Conformation Science animal diseases Mutant Static Electricity Biophysics Mutation Missense General Physics and Astronomy macromolecular substances Fibril medicine.disease_cause Microscopy Atomic Force environment and public health General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Protein structure mental disorders medicine Missense mutation Humans Amino Acid Sequence lcsh:Science Synucleinopathies Mutation Multidisciplinary Chemistry Protein Stability Cryoelectron Microscopy Wild type Acetylation Parkinson Disease General Chemistry Cell biology nervous system diseases 030104 developmental biology Structural biology Amino Acid Substitution nervous system alpha-Synuclein Mutant Proteins lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-9 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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