Kinase Regulation by Hydrophobic Spine Assembly in Cancer
Kinase Regulation by Hydrophobic Spine Assembly in Cancer
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DOI：
10.1128/mcb.00943-14
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发表时间：
2015-01-01
影响因子：
5.3
通讯作者：
Shaw, Andrey S.
中科院分区：
文献类型：
--
作者：
Hu, Jiancheng;Ahuja, Lalima G.;Shaw, Andrey S.
提出了一种基于疏水棘组装的激酶调控新模型。它们位置的变化可以解释激酶活化的机制。在这里，我们研究了人类癌症中的突变，通过最初关注Phe的突变来寻找疏水棘调控的线索。我们在包括BRAF、ABL1和表皮生长因子受体在内的一小组激酶中确定了选定数量的Phe突变。在测试BRAF中的一些突变时，我们发现其中一个突变破坏了ATP结合和催化活性，但促进了非催化变构功能。其他的苯丙氨酸突变可以促进本构催化活性。其中一个突变揭示了一个以前被低估的疏水表面，其功能是定位动态调节α c -螺旋。这支持了c -螺旋作为信号整合基序的关键作用，用于协调激酶的多个元件以创建活性构象。通过研究V600F突变体进一步验证了α - c -螺旋周围疏水空间的重要性，该突变体在缺乏与常见V600E突变相关的负电荷的情况下具有组成性活性。许多疏水突变战略性地定位在c -螺旋上，因此可以驱动激酶激活。
A new model of kinase regulation based on the assembly of hydrophobic spines has been proposed. Changes in their positions can explain the mechanism of kinase activation. Here, we examined mutations in human cancer for clues about the regulation of the hydrophobic spines by focusing initially on mutations to Phe. We identified a selected number of Phe mutations in a small group of kinases that included BRAF, ABL1, and the epidermal growth factor receptor. Testing some of these mutations in BRAF, we found that one of the mutations impaired ATP binding and catalytic activity but promoted noncatalytic allosteric functions. Other Phe mutations functioned to promote constitutive catalytic activity. One of these mutations revealed a previously underappreciated hydrophobic surface that functions to position the dynamic regulatory alpha C-helix. This supports the key role of the C-helix as a signal integration motif for coordinating multiple elements of the kinase to create an active conformation. The importance of the hydrophobic space around the alpha C-helix was further tested by studying a V600F mutant, which was constitutively active in the absence of the negative charge that is associated with the common V600E mutation. Many hydrophobic mutations strategically localized along the C-helix can thus drive kinase activation.