The interaction of alphaB-crystallin with mature alpha-synuclein amyloid fibrils inhibits their elongation.
alphaB-Crystallin is a small heat-shock protein (sHsp) that is colocalized with alpha-synuclein (alphaSyn) in Lewy bodies-the pathological hallmarks of Parkinson's disease-and is an inhibitor of alphaSyn 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 alphaB-crystallin interacts with alphaSyn, 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.
Waudby
Christopher A
CA
University of Cambridge, United Kingdom.
Knowles
Tuomas P J
TP
Devlin
Glyn L
GL
Skepper
Jeremy N
JN
Ecroyd
Heath
H
Carver
John A
JA
Welland
Mark E
ME
Christodoulou
John
J
Dobson
Christopher M
CM
Meehan
Sarah
S
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D052160:Benzothiazoles; D005453:Fluorescence; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018832:Molecular Chaperones / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011791:Quartz; D013844:Thiazoles / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D000682:Amyloid; D052160:Benzothiazoles; D018832:Molecular Chaperones; D013844:Thiazoles; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein; D011791:Quartz; C009462:thioflavin T