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Angew Chem Int Ed Engl. 2014 Jul 14;53(29):7560-3. doi: 10.1002/anie.201400491. Epub 2014 Apr 16.

Co-existence of two different α-synuclein oligomers with different core structures determined by hydrogen/deuterium exchange mass spectrometry.

Author information

1
Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Center for Insoluble Protein Structures (inSPIN), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C (Denmark).

Abstract

Neurodegenerative disorders are characterized by the formation of protein oligomers and amyloid fibrils, which in the case of Parkinson's disease involves the protein α-synuclein (αSN). Cytotoxicity is mainly associated with the oligomeric species, but we still know little about their assembly and structure. Hydrogen/deuterium exchange (HDX) monitored by mass spectrometry is used to analyze oligomers formed by wild-type (wt) αSN and also three familial αSN mutants (A30P, E46K, and A53T). All four variants show co-existence of two different oligomers. The backbone amides of oligomer type I are protected from exchange with D2 O until they dissociate into monomeric αSN by EX1 exchange kinetics. Fewer residues are protected against exchange in oligomer type II, but this type does not revert to αSN monomers. Both oligomers are protected in the core sequence Y39-A89. Based on incubation studies, oligomer type I appears to form straight fibrils, while oligomer type II forms amorphous clusters that do not directly contribute to the fibrillation process.

KEYWORDS:

aggregation; amyloid fibrils; mass spectrometry; oligomers; α-synuclein

PMID:
24740651
DOI:
10.1002/anie.201400491
[Indexed for MEDLINE]

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