The extracellular chaperone clusterin potently inhibits human lysozyme amyloid formation by interacting with prefibrillar species
The extracellular chaperone clusterin potently inhibits human lysozyme amyloid formation by interacting with prefibrillar species
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DOI：
10.1016/j.jmb.2007.02.095
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发表时间：
2007-05-25
影响因子：
5.6
通讯作者：
Dobson, Christopher M.
中科院分区：
文献类型：
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作者：
Kumita, Janet R.;Poon, Stephen;Dobson, Christopher M.
我们研究了细胞外分子伴侣簇蛋白对人溶菌酶突变体（包括与家族性淀粉样蛋白病相关的一种）体外聚集的影响。当凝聚素与溶菌酶的比例低至 1:80（即每 80 个溶菌酶分子 1 个凝聚素分子）时，淀粉样变体 I56T 的聚集就会受到显着抑制。实验表明，在发生聚集抑制的条件下，凝聚素不会与溶菌酶的天然或纤维状状态或已知为聚集反应中关键物质的单体瞬时中间体可检测地结合。相反，它似乎与聚集反应的滞后（成核）阶段以低浓度存在的寡聚物质相互作用。这种行为表明，簇蛋白，或许还有其他细胞外伴侣，可能在减少蛋白质错误折叠和聚集的潜在致病作用方面发挥着关键作用，这些蛋白质（如溶菌酶）被分泌到细胞外环境中。 (c) 2007 Elsevier Ltd. 保留所有权利。
We have studied the effects of the extracellular molecular chaperone, clusterin, on the in vitro aggregation of mutational variants of human lysozyme, including one associated with familial amyloid disease. The aggregation of the amyloidogenic variant I56T is inhibited significantly at clusterin to lysozyme ratios as low as 1:80 (i.e. one clusterin molecule per 80 lysozyme molecules). Experiments indicate that under the conditions where inhibition of aggregation occurs, clusterin does not bind detectably to the native or fibrillar states of lysozyme, or to the monomeric transient intermediate known to be a key species in the aggregation reaction. Rather, it seems to interact with oligomeric species that are present at low concentrations during the lag (nucleation) phase of the aggregation reaction. This behavior suggests that clusterin, and perhaps other extracellular chaperones, could have a key role in curtailing the potentially pathogenic effects of the misfolding and aggregation of proteins that, like lysozyme, are secreted into the extracellular environment. (c) 2007 Elsevier Ltd. All rights reserved.