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首页> 外文期刊>Molecular biology of the cell >Regulation of Chk1 by Its C-terminal Domain
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Regulation of Chk1 by Its C-terminal Domain

机译：Chk1的C末端域的调节。

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摘要

Chk1 is a protein kinase that is the effector molecule in the G2 DNA damage checkpoint. Chk1 homologues have an N-terminal kinase domain, and a C-terminal domain of similar to 200 amino acids that contains activating phosphorylation sites for the ATM/R kinases, though the mechanism of activation remains unknown. Structural studies of the human Chk1 kinase domain show an open conformation; the activity of the kinase domain alone is substantially higher in vitro than full-length Chk1, and coimmunoprecipitation studies suggest the C-terminal domain may contain an autoinhibitory activity. However, we show that truncation of the C-terminal domain inactivates Chk1 in vivo. We identify additional mutations within the C-terminal domain that activate ectopically expressed Chk1 without the need for activating phosphorylation. When expressed from the endogenous locus, activated alleles show a temperature-sensitive loss of function, suggesting these mutations confer a semiactive state to the protein. Intragenic suppressors of these activated alleles cluster to regions in the catalytic domain on the face of the protein that interacts with substrate, suggesting these are the regions that interact with the C-terminal domain. Thus, rather than being an autoinhibitory domain, the C-terminus of Chk1 also contains domains critical for adopting an active configuration.
机译：Chk1是一种蛋白激酶，是G2 DNA损伤检查点中的效应分子。 Chk1同源物具有一个N末端激酶结构域和一个类似于200个氨基酸的C末端结构域，其中包含ATM / R激酶的活化磷酸化位点，尽管活化机理尚不清楚。人类Chk1激酶结构域的结构研究显示一个开放的构象。单独的激酶结构域的活性在体外显着高于全长Chk1，并且免疫共沉淀研究表明C末端结构域可能具有自抑制活性。但是，我们表明，C末端域的截断可在体内灭活Chk1。我们确定了C末端域内的其他突变，这些突变可以激活异位表达的Chk1，而无需激活磷酸化。当从内源基因座表达时，活化的等位基因显示出对温度敏感的功能丧失，表明这些突变赋予蛋白质半活性状态。这些激活的等位基因的基因内抑制子聚集在与底物相互作用的蛋白质表面的催化结构域中的区域，表明这些区域是与C末端结构域相互作用的区域。因此，Chk1的C端不是自抑制域，还包含对于采用主动配置至关重要的域。

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