A chaperone-dependent GSK3β transitional intermediate mediates activation-loop autophosphorylation
A chaperone-dependent GSK3β transitional intermediate mediates activation-loop autophosphorylation
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DOI：
10.1016/j.molcel.2006.10.009
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发表时间：
2006-11-17
期刊：
影响因子：
16
通讯作者：
Cleghon, Vaughn
中科院分区：
文献类型：
--
作者：
Lochhead, Pamela A.;Kinstrie, Ross;Cleghon, Vaughn
糖原合成酶激酶3（GSK 3）是胰岛素和wnt信号通路的关键组分，是不寻常的，因为它是组成性活性的并且响应于上游信号而被抑制。激酶活性被认为通过激活环中酪氨酸的分子内磷酸化（GSK 3 β中的Y216）而增加，其时间和机制尚未确定。我们发现，GSK 3 β自磷酸化Y216作为一种分子伴侣依赖性过渡中间体，具有分子内酪氨酸激酶活性，并显示出不同的敏感性相比，成熟的GSK 3 β的小分子抑制剂。自磷酸化后，成熟的GSK 3 β是分子间丝氨酸/苏氨酸激酶，不再需要伴侣。这表明自激活激酶采用不同的分子机制进行自磷酸化;对于激酶如GSK 3，仅影响过渡中间体的抑制剂在常规药物筛选中会被遗漏。
Glycogen synthase kinase 3 (GSK3), a key component of the insulin and wnt signaling pathways, is unusual, as it is constitutively active and is inhibited in response to upstream signals. Kinase activity is thought to be increased by intramolecular phosphorylation of a tyrosine in the activation loop (Y216 in GSK3 beta), whose timing and mechanism is undefined. We show that GSK3 beta autophosphorylates Y216 as a chaperone-dependent transitional intermediate possessing intramolecular tyrosine kinase activity and displaying different sensitivity to small-molecule inhibitors compared to mature GSK3 beta. After autophosphorylation, mature GSK3 beta is then an intermolecular serine/threonine kinase no longer requiring a chaperone. This shows that autoactivating kinases have adopted different molecular mechanisms for autophosphorylation; and for kinases such as GSK3, inhibitors that affect only the transitional intermediate would be missed in conventional drug screens.