Journal
BIOPHYSICAL JOURNAL
Volume 98, Issue 5, Pages 843-851Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2009.10.056
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Funding
- Unilever and the Biotechnology
- Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Interdisciplinary Research Council in Nanotechnology
- National Health and Medical Research Council of Australia
- C.J. Martin Fellowship
- Peter Doherty Fellowship
- Australian Research Council
- Wellcome Trust
- Leverhulme Trust
- Royal Society Dorothy Hodgkin Fellowship
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alpha B-Crystallin is a small heat-shock protein (sHsp) that is colocalized with alpha-synuclein (alpha Syn) in Lewy bodies-the pathological hallmarks of Parkinson's disease-and is an inhibitor of alpha Syn amyloid fibril formation in an ATP-independent manner in vitro. We have investigated the mechanism underlying the inhibitory action of sHsps, and here we establish, by means of a variety of biophysical techniques including immunogold labeling and nuclear magnetic resonance spectroscopy, that alpha B-crystallin interacts with alpha Syn, binding along the length of mature amyloid fibrils. By measurement of seeded fibril elongation kinetics, both in solution and on a surface using a quartz crystal microbalance, this binding is shown to strongly inhibit further growth of the fibrils. The binding is also demonstrated to shift the monomer-fibril equilibrium in favor of dissociation. We believe that this mechanism, by which a sHsp interacts with mature amyloid fibrils, could represent an additional and potentially generic means by which at least some chaperones protect against amyloid aggregation and limit the onset of misfolding diseases.
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