Ack1: activation and regulation by allostery.
Ack1: activation and regulation by allostery.
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DOI：
10.1371/journal.pone.0053994
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Gajiwala KS;Maegley K;Ferre R;He YA;Yu X
非受体酪氨酸激酶Ack 1属于一个独特的多结构域蛋白激酶家族，即Ack。Ack是唯一一个在激酶结构域之后具有SH 3结构域的含有SH 3结构域的激酶家族;其他激酶在激酶结构域之前具有它们的SH 3结构域。以前的报道表明，Ack 1不需要磷酸化激活，并且分离的激酶结构域的酶活性相对于其他激酶较低。它已被证明在细胞环境中二聚化，这增强了其酶活性。然而，激活的分子机制仍然未知。在这里，我们提出了Ack 1激酶结构域，激酶结构域+SH 3结构域的结构和生化数据，表明Ack 1在其单体状态下是自抑制的，像EGFR和CDK。激酶结构域的激活可能需要N端半段介导的对称二聚化，这可能由N端SAM结构域促进。这里提出的结果表明，SH 3结构域，不像Src家族酪氨酸激酶，不直接控制酶的活化状态。相反，我们推测SH 3结构域可能通过促进MIG 6同源区与激酶结构域的结合而发挥调节作用。我们假设Ack 1的激活和调节功能与受体酪氨酸激酶EGFR的激活和调节功能相似，但存在一些有趣的差异。
The non-receptor tyrosine kinase Ack1 belongs to a unique multi-domain protein kinase family, Ack. Ack is the only family of SH3 domain containing kinases to have an SH3 domain following the kinase domain; others have their SH3 domains preceding the kinase domain. Previous reports have suggested that Ack1 does not require phosphorylation for activation and the enzyme activity of the isolated kinase domain is low relative to other kinases. It has been shown to dimerize in the cellular environment, which augments its enzyme activity. The molecular mechanism of activation, however, remains unknown. Here we present structural and biochemical data on Ack1 kinase domain, and kinase domain+SH3 domain that suggest that Ack1 in its monomeric state is autoinhibited, like EGFR and CDK. The activation of the kinase domain may require N-lobe mediated symmetric dimerization, which may be facilitated by the N-terminal SAM domain. Results presented here show that SH3 domain, unlike in Src family tyrosine kinases, does not directly control the activation state of the enzyme. Instead we speculate that the SH3 domain may play a regulatory role by facilitating binding of the MIG6 homologous region to the kinase domain. We postulate that features of Ack1 activation and regulation parallel those of receptor tyrosine kinase EGFR with some interesting differences.
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影响因子：
64.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.0700420104
发表时间：
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影响因子：
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作者：
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Stout, TJ
DOI：
10.1073/pnas.0703854104
发表时间：
2007-12-04
影响因子：
11.1
作者：
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通讯作者：
Carpenter, Graham