Structural Basis of Membrane Targeting by the Phox Homology Domain of Cytokine-independent Survival Kinase (CISK-PX)*
Structural Basis of Membrane Targeting by the Phox Homology Domain of Cytokine-independent Survival Kinase (CISK-PX)*
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DOI：
10.1074/jbc.m404107200
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发表时间：
2004-07
影响因子：
4.8
通讯作者：
Y. Xing;Dan Liu;Rong-guang Zhang;A. Joachimiak;Songyang Zhou;Wenqing Xu
中科院分区：
文献类型：
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作者：
Y. Xing;Dan Liu;Rong-guang Zhang;A. Joachimiak;Songyang Zhou;Wenqing Xu
血清中的细胞因子非依赖性生存激酶（CISK）和糖皮质激素调节激酶家族在介导细胞生长和生存中发挥着重要作用。 CISK 的催化激酶结构域的 N 端含有 phox 同源 (PX) 结构域，这是一种磷酸肌醇结合基序，可指导 CISK 的膜定位并调节 CISK 活性。我们确定了小鼠 CISK-PX 结构域的晶体结构，以揭示 CISK 膜靶向的结构基础。除了磷酸肌醇结合袋赋予的特定相互作用之外，该结构表明疏水性环区域和亲水性β-转角有助于与膜的相互作用。此外，生化研究表明，CISK-PX 在 PX 结构域和激酶结构域之间存在连接子的情况下二聚化，表明 CISK 膜定位的多价机制。
The cytokine-independent survival kinase (CISK) in the serum and glucocorticoid-regulated kinase family plays an important role in mediating cell growth and survival. N-terminal to its catalytic kinase domain, CISK contains a phox homology (PX) domain, a phosphoinositide-binding motif that directs the membrane localization of CISK and regulates CISK activity. We have determined the crystal structures of the mouse CISK-PX domain to unravel the structural basis of membrane targeting of CISK. In addition to the specific interactions conferred by the phosphoinositide-binding pocket, the structure suggests that a hydrophobic loop region and a hydrophilic β-turn contribute to the interactions with the membrane. Furthermore, biochemical studies reveal that CISK-PX dimerizes in the presence of the linker between the PX domain and kinase domain, suggesting a multivalent mechanism in membrane localization of CISK.