Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.
Increased monomerization of mutant HSPB1 leads to protein hyperactivity in Charcot-Marie-Tooth neuropathy.
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DOI：
10.1074/jbc.m109.082644
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发表时间：
2010-04-23
期刊：
影响因子：
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通讯作者：
Janssens S
中科院分区：
文献类型：
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作者：
Almeida-Souza L;Goethals S;de Winter V;Dierick I;Gallardo R;Van Durme J;Irobi J;Gettemans J;Rousseau F;Schymkowitz J;Timmerman V;Janssens S
小分子热休克蛋白是一种分子伴侣，能够维持变性蛋白处于折叠能力状态。我们之前已经证明，小热休克蛋白HSPB1(HSP27)的错义突变会导致远端遗传性运动神经病和轴突性Charcot-Marie-Tooth病。在这里，我们调查了已知导致周围神经病变的HSPB1突变的生化后果。与其他伴侣病症相比，我们的结果显示特定的HSPB1突变与野生型相比表现出更高的伴侣活性。HSPB1的过度激活伴随着从野生型二聚体状态到单体状态的变化，而不解离24-Meric状态。对野生型和HSPB1突变体的蛋白质复合体的纯化表明，高活性的异构体也表现出与客户蛋白的增强结合。此外，我们还发现野生型HSPB1蛋白在热休克激活过程中经历了单体作用，这有力地表明该单体是HSPB1蛋白的活性形式。
Small heat shock proteins are molecular chaperones capable of maintaining denatured proteins in a folding-competent state. We have previously shown that missense mutations in the small heat shock protein HSPB1 (HSP27) cause distal hereditary motor neuropathy and axonal Charcot-Marie-Tooth disease. Here we investigated the biochemical consequences of HSPB1 mutations that are known to cause peripheral neuropathy. In contrast to other chaperonopathies, our results revealed that particular HSPB1 mutations presented higher chaperone activity compared with wild type. Hyperactivation of HSPB1 was accompanied by a change from its wild-type dimeric state to a monomer without dissociation of the 24-meric state. Purification of protein complexes from wild-type and HSPB1 mutants showed that the hyperactive isoforms also presented enhanced binding to client proteins. Furthermore, we show that the wild-type HSPB1 protein undergoes monomerization during heat-shock activation, strongly suggesting that the monomer is the active form of the HSPB1 protein.