Structural basis for the inhibition of tyrosine kinase activity of ZAP-70
Structural basis for the inhibition of tyrosine kinase activity of ZAP-70
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DOI：
10.1016/j.cell.2007.03.039
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发表时间：
2007-05-18
期刊：
影响因子：
64.5
通讯作者：
Kuriyan, John
中科院分区：
文献类型：
--
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
ZAP-70是T细胞抗原受体信号传导所需的细胞质酪氨酸激酶，由包括负责结合免疫受体酪氨酸活化基序（ITAM）的串联SH 2单元的调节区段控制。自抑制ZAP-70的晶体结构表明，非活性激酶结构域采用类似于细胞周期蛋白依赖性激酶和Src激酶的构象。然而，ZAP-70的自身抑制机制是不同的，并且涉及调节区段与激酶结构域的铰链区之间的相互作用，这降低了其灵活性。当磷酸化时激活ZAP-70的SH 2-激酶接头中的两个酪氨酸残基参与将接头连接到激酶结构域的芳香族-芳香族相互作用。这些相互作用与ITAM结合是不一致的，表明这种自抑制ZAP-70构象的不稳定是激酶激活的第一步。
ZAP-70, a cytoplasmic tyrosine kinase required for T cell antigen receptor signaling, is controlled by a regulatory segment that includes a tandem SH2 unit responsible for binding to immunoreceptor tyrosine-based activation motifs (ITAMs). The crystal structure of autoinhibited ZAP-70 reveals that the inactive kinase domain adopts a conformation similar to that of cyclin-dependent kinases and Src kinases. The auto-inhibitory mechanism of ZAP-70 is, however, distinct and involves interactions between the regulatory segment and the hinge region of the kinase domain that reduce its flexibility. Two tyrosine residues in the SH2-kinase linker that activate ZAP-70 when phosphorylated are involved in aromatic-aromatic interactions that connect the linker to the kinase domain. These interactions are inconsistent with ITAM binding, suggesting that destabilization of this autoinhibited ZAP-70 conformation is the first step in kinase activation.