High-Affinity Amphipathic Modulators of Amyloid Fibril Nucleation and Elongation
The misfolding and aggregation of proteins to form amyloid fibrils are associated with a number of debilitating, age-related diseases. Many of the proteins that form amyloid in vivo are lipid-binding proteins, accounting for the significant impact of lipids on the rate of formation and morphology of...
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Published in | Journal of molecular biology Vol. 406; no. 3; pp. 416 - 429 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Ltd
25.02.2011
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Subjects | |
Online Access | Get full text |
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Summary: | The misfolding and aggregation of proteins to form amyloid fibrils are associated with a number of debilitating, age-related diseases. Many of the proteins that form amyloid in vivo are lipid-binding proteins, accounting for the significant impact of lipids on the rate of formation and morphology of amyloid fibrils. To systematically investigate the effect of lipid-like compounds, we screened a range of amphipathic lipids and detergents for their effect on amyloid fibril formation by human apolipoprotein (apo) C-II. The initial screen, conducted using a set of amphiphiles at half critical micelle concentration, identified several activators and inhibitors that were selected for further analysis. Sedimentation analysis and circular dichroism studies of apoC-II at low, non-fibril-forming concentrations (0.05 mg/ml) revealed that all of the inhibitors induced the formation of apoC-II dimers enriched in α-helical content while the activators promoted the formation of stable apoC-II tetramers with increased β-structure. Kinetic analysis identified modulators of apoC-II fibril formation that were effective at concentrations as low as 10 μM, corresponding to a modulator-to-apoC-II ratio of approximately 1:10. Delayed addition of the test compounds after fibril formation had commenced allowed the effects of selected amphiphiles on fibril elongation to be determined separately from their effects on fibril nucleation. The results indicated that specific amphiphiles induce structural changes in apoC-II that cause separate and independent effects on fibril nucleation and elongation. Low-molecular-weight amphipathic lipids and detergents may serve as useful, stage-specific modulators of protein self-assembly and fibril formation in disease-prevention strategies.
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► We screened amphiphiles for their effect on apo C-II amyloid fibril formation. ► Several activators and inhibitors acted at submicellar concentrations. ► Activators promoted tetrameric β-rich intermediates. ► Inhibitors induced apoC-II dimers with increased α-structure. ► Modulators exerted independent effects on fibril nucleation and elongation. |
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Bibliography: | http://dx.doi.org/10.1016/j.jmb.2010.12.023 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 0022-2836 1089-8638 |
DOI: | 10.1016/j.jmb.2010.12.023 |