Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils
Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils
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DOI：
10.1096/fj.12-220657
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发表时间：
2013-03-01
期刊：
影响因子：
4.8
通讯作者：
Griffin, Michael D. W.
中科院分区：
文献类型：
--
作者：
Binger, Katrina J.;Ecroyd, Heath;Griffin, Michael D. W.
蛋白质在体内聚集成淀粉样纤维表明，通常阻止或逆转这种聚集的细胞机制已经失败。热休克小分子伴侣蛋白αB-晶状体蛋白(αB-c)抑制淀粉样蛋白的形成，并与淀粉样斑块共定位，但其定位的生理原因尚不清楚。在这里，我们使用载脂蛋白C-II(apoC-II)作为一个模型纤维形成系统，我们证明了αB-c直接与成熟的淀粉样蛋白纤维结合(K-d 5.4+/-0.5um M)。在这样做的过程中，αB-c稳定了原纤维的稀释诱导的碎裂，阻止了部分形成的原纤维的伸长，并促进了成熟的原纤维解离成可溶的单体。此外，在没有稀释的情况下，αB-c与apoC-II纤维的结合导致平均聚集体尺寸增加14倍，导致大的纤维缠结使人联想到蛋白质包裹体。我们认为，αB-c与纤维的结合防止了碎裂，并介导了纤维与大包裹体的横向结合。我们进一步假设，apoC-II与αB-c的瞬时相互作用诱导了一种不具纤维功能的单体apoC-II形式，防止了寡聚并促进了纤维的解离。这项工作揭示了先前未知的阿尔法B-C伴侣在淀粉样蛋白组装和纤维动力学中的作用机制，并为小分子热休克蛋白与淀粉样蛋白沉积在体内的共存提供了理论基础。-Binger，K.J.，Ecroyd，H.，Yang，S.，Carver，J.A.，Howlett，G.J.，Griffin，M.D.W.避免寡聚状态：阿尔法B-晶体蛋白抑制碎裂并诱导载脂蛋白C-II淀粉样纤维解离。FASE B J.27,1214-1222(2013)。Www.fasebj.org
The in vivo aggregation of proteins into amyloid fibrils suggests that cellular mechanisms that normally prevent or reverse this aggregation have failed. The small heat-shock molecular chaperone protein alpha B-crystallin (alpha B-c) inhibits amyloid formation and colocalizes with amyloid plaques; however, the physiological reason for this localization remains unexplored. Here, using apolipoprotein C-II (apoC-II) as a model fibril-forming system, we show that alpha B-c binds directly to mature amyloid fibrils (K-d 5.4 +/- 0.5 mu M). In doing so, alpha B-c stabilized the fibrils from dilution-induced fragmentation, halted elongation of partially formed fibrils, and promoted the dissociation of mature fibrils into soluble monomers. Moreover, in the absence of dilution, the association of alpha B-c with apoC-II fibrils induced a 14-fold increase in average aggregate size, resulting in large fibrillar tangles reminiscent of protein inclusions. We propose that the binding of alpha B-c to fibrils prevents fragmentation and mediates the lateral association of fibrils into large inclusions. We further postulate that transient interactions of apoC-II with alpha B-c induce a fibril-incompetent monomeric apoC-II form, preventing oligomerization and promoting fibril dissociation. This work reveals previously unrecognized mechanisms of alpha B-c chaperone action in amyloid assembly and fibril dynamics, and provides a rationale for the in vivo colocalization of small heat-shock proteins with amyloid deposits.-Binger, K. J., Ecroyd, H., Yang, S., Carver, J. A., Howlett, G. J., Griffin, M. D. W. Avoiding the oligomeric state: alpha B-crystallin inhibits fragmentation and induces dis-sociation of apolipoprotein C-II amyloid fibrils. FASEB J. 27, 1214-1222 (2013). www.fasebj.org