Diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy

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DOIResolve DOI: http://doi.org/10.1371/journal.pone.0086495
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TypeArticle
Journal titlePLoS ONE
ISSN1932-6203
Volume9
Issue1
Article numbere86495
Subjectalpha synuclein; dimer; monomer; oligomer; tetramer; animal cell; article; controlled study; enzyme kinetics; mathematical computing; molecular probe; molecular stability; nonhuman; oligomerization; optical tweezers; Parkinson disease; particle size; protein aggregation; protein stability; protein structure; single molecule force spectroscopy; spectroscopy
AbstractOligomeric aggregates are widely suspected as toxic agents in diseases caused by protein aggregation, yet they remain poorly characterized, partly because they are challenging to isolate from a heterogeneous mixture of species. We developed an assay for characterizing structure, stability, and kinetics of individual oligomers at high resolution and sensitivity using single-molecule force spectroscopy, and applied it to observe the formation of transient structured aggregates within single oligomers of α-synuclein, an intrinsically-disordered protein linked to Parkinson's disease. Measurements of the molecular extension as the proteins unfolded under tension in optical tweezers revealed that even small oligomers could form numerous metastable structures, with a surprisingly broad range of sizes. Comparing the structures formed in monomers, dimers and tetramers, we found that the average mechanical stability increased with oligomer size. Most structures formed within a minute, with size-dependent rates. These results provide a new window onto the complex α-synuclein aggregation landscape, characterizing the microscopic structural heterogeneity and kinetics of different pathways. © 2014 Neupane et al.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); National Institute for Nanotechnology (NINT-INNT)
Peer reviewedYes
NPARC number21272128
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Record identifiere10fd22b-612e-4048-861b-dba88e3a7f9d
Record created2014-07-23
Record modified2016-05-09
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