8BQW

Cryo-EM structure of alpha-synuclein filaments doublet from Juvenile-onset synucleinopathy

Summary for 8BQW

• Entry DOI: 10.2210/pdb8bqw/pdb
• EMDB information: 16189
• Descriptor: Alpha-synuclein, Unknown protein (3 entities in total)
• Functional Keywords: alpha-synuclein, amyloid, fibril, insertion, juvenile-onset synucleinopathy (jos), synucleinopathy, protein fibril
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 30520.13

Authors

Yang, Y.,Garringer, J.H.,Shi, Y.,Lovestam, S.,Peak-Chew, S.Y.,Zhang, X.J.,Kotecha, A.,Bacioglu, M.,Koto, A.,Takao, M.,Spillantini, G.M.,Ghetti, B.,Vidal, R.,Murzin, G.A.,Scheres, H.W.S.,Goedert, M. (deposition date: 2023-01-18, release date: 2023-02-22, Last modification date: 2024-07-24)

Primary citation

Yang, Y.,Garringer, H.J.,Shi, Y.,Lovestam, S.,Peak-Chew, S.,Zhang, X.,Kotecha, A.,Bacioglu, M.,Koto, A.,Takao, M.,Spillantini, M.G.,Ghetti, B.,Vidal, R.,Murzin, A.G.,Scheres, S.H.W.,Goedert, M.
New SNCA mutation and structures of alpha-synuclein filaments from juvenile-onset synucleinopathy.
Acta Neuropathol, 145:561-572, 2023

PubMed Abstract: A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

PubMed: 36847833
DOI: 10.1007/s00401-023-02550-8

Experimental method

ELECTRON MICROSCOPY (2.3 Å)