Structural basis for syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide
Structural basis for syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide
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DOI：
10.1006/jmbi.1998.1964
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发表时间：
1998-08-21
影响因子：
5.6
通讯作者：
Waksman, G
中科院分区：
文献类型：
--
作者：
F端tterer, K;Wong, J;Waksman, G
由ZAP-70和Syk组成的Syk激酶家族在多种免疫和非免疫细胞中发挥重要作用。该激酶家族的特征在于存在两个相邻的SH 2结构域，其通过受体编码的酪氨酸磷酸化基序介导其定位于膜。虽然这两种激酶共享许多结构和功能特征，但Syk的更普遍的性质表明，这种激酶可以容纳更多种类的基序来介导其功能。我们目前的晶体结构的串联SH 2结构域的Syk复合的双重磷酸化ITAM肽。通过在3.0埃分辨率下的多个同晶置换解析结构。不对称单位包括六个拷贝的配体蛋白，揭示了一个令人惊讶的灵活性，在两个SH 2结构域的相对方向。C-末端磷酸酪氨酸结合位点与ZAP-70的等效区域非常不同，这表明与ZAP-70相反，Syk的两个SH 2结构域可以作为独立的单元起作用。Syk的SH 2模块的构象灵活性和结构独立性可能为Syk在各种信号转导途径中更普遍参与提供了分子基础。(C)北京：科学出版社.
The Syk family of kinases, consisting of ZAP-70 and Syk, play essential roles in a variety of immune and non-immune cells. This family of kinases is characterized by the presence of two adjacent SH2 domains which mediate their localization to the membrane through receptor encoded tyrosine phosphorylated motifs. While these two kinases share many structural and functional features, the more ubiquitous nature of Syk has suggested that this kinase may accommodate a greater variety of motifs to mediate its function. We present the crystal structure of the tandem SH2 domain of Syk complexed with a dually phosphorylated ITAM peptide. The structure was solved by multiple isomorphous replacement at 3.0 Angstrom resolution. The asymmetric unit comprises six copies of the liganded protein, revealing a surprising flexibility in the relative orientation of the two SH2 domains. The C-terminal phosphotyrosine-binding site is very different from the equivalent region of ZAP-70, suggesting that in contrast to ZAP-70, the two SH2 domains of Syk can function as independent units. The conformational flexibility and structural independence of the SH2 modules of Syk likely provides the molecular basis for the more ubiquitous involvement of Syk in a variety of signal transduction pathways. (C) 1998 Academic Press.