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Structure and dynamics of oligomeric intermediates in ?2-microglobulin self-assembly.


ABSTRACT: ?(2)-Microglobulin is a 99-residue protein with a propensity to form amyloid-like fibrils in vitro which exhibit distinct morphologies dependent on the solution conditions employed. Here we have used ion mobility spectrometry-mass spectrometry to characterize the oligomeric species detected during the formation of worm-like fibrils of ?(2)-microglobulin at pH 3.6. Immediately upon sample dissolution, ?(2)-microglobulin monomer and oligomers-the latter ranging in size from dimer to hexamer-are present as a pool of rapidly interconverting species. Increasing the ionic strength of the solution initiates fibril formation without a lag-phase whereupon these oligomers become more stable and higher-order species (7-mer to >14-mer) are observed. The oligomers detected have collision cross-sectional areas consistent with a linearly stacked assembly comprising subunits of native-like volume. The results provide insights into the identity and properties of the transient, oligomeric intermediates formed during assembly of worm-like fibrils and identify species that differ significantly from the oligomers previously characterized during the nucleated assembly of long, straight fibrils. The data presented demonstrate the interrelationship between different fibril-forming pathways and identify their points of divergence.

SUBMITTER: Smith DP 

PROVIDER: S-EPMC3164137 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Structure and dynamics of oligomeric intermediates in β2-microglobulin self-assembly.

Smith David P DP   Woods Lucy A LA   Radford Sheena E SE   Ashcroft Alison E AE  

Biophysical journal 20110901 5


β(2)-Microglobulin is a 99-residue protein with a propensity to form amyloid-like fibrils in vitro which exhibit distinct morphologies dependent on the solution conditions employed. Here we have used ion mobility spectrometry-mass spectrometry to characterize the oligomeric species detected during the formation of worm-like fibrils of β(2)-microglobulin at pH 3.6. Immediately upon sample dissolution, β(2)-microglobulin monomer and oligomers-the latter ranging in size from dimer to hexamer-are pr  ...[more]

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