Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation
The molecular chaperone alpha B-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with A beta amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether th...
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ftucl:oai:eprints.ucl.ac.uk.OAI2:1326513 2023-05-15T15:10:06+02:00 Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation Shammas, SL Waudby, CA Wang, SY Buell, AK Knowles, TPJ Ecroyd, H Welland, ME Carver, JA Dobson, CM Meehan, S 2011-10-05 http://discovery.ucl.ac.uk/1326513/ unknown CELL PRESS BIOPHYS J , 101 (7) 1681 - 1689. (2011) HEAT-SHOCK-PROTEIN FAMILIAL ALZHEIMERS-DISEASE IN-VITRO DIFFUSIBLE LIGANDS AGGREGATION LENS OLIGOMERS EXPRESSION PEPTIDE GROWTH Article 2011 ftucl 2013-11-10T04:57:32Z The molecular chaperone alpha B-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with A beta amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with A beta fibrils in vitro. We find that alpha B-crystallin binds to wild-type A beta(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of A beta(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of alpha B-crystallin on the seeded growth of A beta fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of alpha B-crystallin to seed fibrils strongly inhibits their elongation. Because the lag phase in sigmoidal fibril assembly kinetics is dominated by elongation and fragmentation rates, the chaperone mechanism identified here represents a highly effective means to inhibit fibril proliferation. Together with previous observations of alpha B-crystallin interaction with alpha-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation. Article in Journal/Newspaper Arctic University College London: UCL Discovery Arctic |
institution |
Open Polar |
collection |
University College London: UCL Discovery |
op_collection_id |
ftucl |
language |
unknown |
topic |
HEAT-SHOCK-PROTEIN FAMILIAL ALZHEIMERS-DISEASE IN-VITRO DIFFUSIBLE LIGANDS AGGREGATION LENS OLIGOMERS EXPRESSION PEPTIDE GROWTH |
spellingShingle |
HEAT-SHOCK-PROTEIN FAMILIAL ALZHEIMERS-DISEASE IN-VITRO DIFFUSIBLE LIGANDS AGGREGATION LENS OLIGOMERS EXPRESSION PEPTIDE GROWTH Shammas, SL Waudby, CA Wang, SY Buell, AK Knowles, TPJ Ecroyd, H Welland, ME Carver, JA Dobson, CM Meehan, S Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
topic_facet |
HEAT-SHOCK-PROTEIN FAMILIAL ALZHEIMERS-DISEASE IN-VITRO DIFFUSIBLE LIGANDS AGGREGATION LENS OLIGOMERS EXPRESSION PEPTIDE GROWTH |
description |
The molecular chaperone alpha B-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with A beta amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with A beta fibrils in vitro. We find that alpha B-crystallin binds to wild-type A beta(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of A beta(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of alpha B-crystallin on the seeded growth of A beta fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of alpha B-crystallin to seed fibrils strongly inhibits their elongation. Because the lag phase in sigmoidal fibril assembly kinetics is dominated by elongation and fragmentation rates, the chaperone mechanism identified here represents a highly effective means to inhibit fibril proliferation. Together with previous observations of alpha B-crystallin interaction with alpha-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation. |
format |
Article in Journal/Newspaper |
author |
Shammas, SL Waudby, CA Wang, SY Buell, AK Knowles, TPJ Ecroyd, H Welland, ME Carver, JA Dobson, CM Meehan, S |
author_facet |
Shammas, SL Waudby, CA Wang, SY Buell, AK Knowles, TPJ Ecroyd, H Welland, ME Carver, JA Dobson, CM Meehan, S |
author_sort |
Shammas, SL |
title |
Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
title_short |
Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
title_full |
Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
title_fullStr |
Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
title_full_unstemmed |
Binding of the Molecular Chaperone alpha B-Crystallin to A beta Amyloid Fibrils Inhibits Fibril Elongation |
title_sort |
binding of the molecular chaperone alpha b-crystallin to a beta amyloid fibrils inhibits fibril elongation |
publisher |
CELL PRESS |
publishDate |
2011 |
url |
http://discovery.ucl.ac.uk/1326513/ |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
BIOPHYS J , 101 (7) 1681 - 1689. (2011) |
_version_ |
1766341160147615744 |