Resolution of oligomeric species during the aggregation of Aβ1-40 using (19)F NMR.

Abstract:

:In the commonly used nucleation-dependent model of protein aggregation, aggregation proceeds only after a lag phase in which the concentration of energetically unfavorable nuclei reaches a critical value. The formation of oligomeric species prior to aggregation can be difficult to detect by current spectroscopic techniques. By using real-time (19)F NMR along with other techniques, we are able to show that multiple oligomeric species can be detected during the lag phase of Aβ1-40 fiber formation, consistent with a complex mechanism of aggregation. At least six types of oligomers can be detected by (19)F NMR. These include the reversible formation of large β-sheet oligomer immediately after solubilization at high peptide concentration, a small oligomer that forms transiently during the early stages of the lag phase, and four spectroscopically distinct forms of oligomers with molecular weights between ∼30 and 100 kDa that appear during the later stages of aggregation. The ability to resolve individual oligomers and track their formation in real-time should prove fruitful in understanding the aggregation of amyloidogenic proteins and in isolating potentially toxic nonamyloid oligomers.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Suzuki Y,Brender JR,Soper MT,Krishnamoorthy J,Zhou Y,Ruotolo BT,Kotov NA,Ramamoorthy A,Marsh EN

doi

10.1021/bi400027y

subject

Has Abstract

pub_date

2013-03-19 00:00:00

pages

1903-12

issue

11

eissn

0006-2960

issn

1520-4995

journal_volume

52

pub_type

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