共 76 条
Binding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation
被引:137
作者:

Shammas, Sarah L.
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Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Waudby, Christopher A.
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机构:
UCL, Dept Struct Mol Biol, London, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Wang, Shuyu
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机构:
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Buell, Alexander K.
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Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Knowles, Tuomas P. J.
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机构:
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Ecroyd, Heath
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机构:
Univ Wollongong, Sch Biol Sci, Wollongong, NSW, Australia Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Welland, Mark E.
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h-index: 0
机构:
Univ Cambridge, Nanosci Ctr, Cambridge, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Carver, John A.
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h-index: 0
机构:
Univ Adelaide, Sch Chem & Phys, Adelaide, SA, Australia Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Dobson, Christopher M.
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h-index: 0
机构:
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

Meehan, Sarah
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h-index: 0
机构:
Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
机构:
[1] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
[2] Univ Cambridge, Nanosci Ctr, Cambridge, England
[3] UCL, Dept Struct Mol Biol, London, England
[4] Univ Wollongong, Sch Biol Sci, Wollongong, NSW, Australia
[5] Univ Adelaide, Sch Chem & Phys, Adelaide, SA, Australia
基金:
英国工程与自然科学研究理事会;
澳大利亚研究理事会;
英国生物技术与生命科学研究理事会;
英国医学研究理事会;
关键词:
HEAT-SHOCK-PROTEIN;
FAMILIAL ALZHEIMERS-DISEASE;
IN-VITRO;
DIFFUSIBLE LIGANDS;
AGGREGATION;
LENS;
OLIGOMERS;
EXPRESSION;
PEPTIDE;
GROWTH;
D O I:
10.1016/j.bpj.2011.07.056
中图分类号:
Q6 [生物物理学];
学科分类号:
071011 ;
摘要:
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.
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页码:1681 / 1689
页数:9
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Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Alzheimers Res Lab, Tampa, FL USA Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden

Morgan, Dave
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Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Alzheimers Res Lab, Tampa, FL USA Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden

Lannfelt, Lars
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Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden

Pettersson, Frida E.
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Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden

Nilsson, Lars N. G.
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Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden Uppsala Univ, Rudbeck Lab, Dept Publ Hlth & Caring Sci Mol Geriatr, S-75185 Uppsala, Sweden