Binding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation

被引:137
作者
Shammas, Sarah L. [1 ]
Waudby, Christopher A. [3 ]
Wang, Shuyu [1 ]
Buell, Alexander K. [1 ]
Knowles, Tuomas P. J. [1 ]
Ecroyd, Heath [4 ]
Welland, Mark E. [2 ]
Carver, John A. [5 ]
Dobson, Christopher M. [1 ]
Meehan, Sarah [1 ]
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.
引用
收藏
页码:1681 / 1689
页数:9
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