CASK point mutation regulates protein-protein interactions and NR2b promoter activity
CASK point mutation regulates protein-protein interactions and NR2b promoter activity
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DOI：
10.1016/j.bbrc.2009.03.015
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发表时间：
2009-04-24
影响因子：
3.1
通讯作者：
Hsueh, Yi-Ping
中科院分区：
文献类型：
--
作者：
Huang, Tzyy-Nan;Hsueh, Yi-Ping
CASK基因突变可导致人类智力迟钝和小头畸形，提示CASK在大脑中发挥重要作用。小鼠CASK基因敲除导致新生儿死亡，这使得在小鼠模型中的进一步阐明变得困难。由于CASK最初被鉴定为多结构域接头蛋白，因此鉴定中断特定蛋白质相互作用的点突变将有助于解剖其分子功能。研究表明，大鼠CASK鸟苷酸激酶（GK）结构域的Thr-to-Ala突变可减少CASK与两种关键脑蛋白Tbr-1和CINAP之间的相互作用。这种影响是特异性的：这种突变不影响通过GK结构域发生的CASK二聚化。Tbr-1-CASK-CINAP复合体调节NMDA受体亚基2b （NR2b）的表达，我们发现这种点突变也影响NR2b启动子的活性。该突变的发现为进一步解剖CASK在脑中的功能提供了可能。(C) 2009爱思唯尔公司版权所有。
Mutations in the CASK gene result in mental retardation and microcephaly in humans, suggesting an important role for CASK in brain. CASK gene knockout in mice causes neonatal lethality, making further elucidation in mouse models difficult. Because CASK was originally identified as a multidomain adaptor protein, identifying a point mutation interrupting a specific protein interaction Would be useful in dissecting its molecular function. Here, a Thr-to-Ala mutation in the rat CASK guanylate kinase (GK) domain was shown to reduce interactions among CASK and Tbr-1 and CINAP, two critical brain proteins. The effect is specific: this mutation does not affect CASK dimerization that occurs via the GK domain. The Tbr-1-CASK-CINAP complex regulates expression of the NMDA receptor subunit-2b (NR2b), and we show that this point mutation also affects NR2b promoter activity. The identification of this mutation may make it possible to further dissect the function of CASK in brain. (C) 2009 Elsevier Inc. All rights reserved.