Binding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation
Binding of the Molecular Chaperone αB-Crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation
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DOI：
10.1016/j.bpj.2011.07.056
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发表时间：
2011-10-05
影响因子：
3.4
通讯作者：
Meehan, Sarah
中科院分区：
文献类型：
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作者：
Shammas, Sarah L.;Waudby, Christopher A.;Meehan, Sarah
分子伴侣α B-晶状体蛋白是一种小的热休克蛋白，其响应于多种应激刺激而上调，并且发现与阿尔茨海默病特征性的细胞外斑块中的A β淀粉样蛋白原纤维共定位。我们研究了这种典型的小的热休克蛋白是否具有在体外与A β纤维相互作用的能力。我们发现α B-晶体蛋白以微摩尔亲和力结合野生型A β（42）原纤维，并且还结合由A β（42）的E22 G Arctic突变形成的原纤维。免疫电子显微镜证实，结合发生沿着整个长度和纤维的末端。研究了α-B-晶状体蛋白对A β原纤维在溶液中和石英晶体微天平生物传感器表面上的种子生长的影响，揭示了α-B-晶状体蛋白与种子原纤维的结合强烈抑制了它们的伸长。由于S形原纤维组装动力学中的滞后期由伸长和片段化速率主导，因此本文鉴定的伴侣机制代表了抑制原纤维增殖的高效手段。连同先前观察到的α-B-晶状体蛋白与α-突触核蛋白和胰岛素原纤维的相互作用，结果表明，这种机制是一种通用的手段，提供分子伴侣保护淀粉样蛋白原纤维的形成。
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.