Fütterer K, Wong J, Grucza R A, Chan A C, Waksman G
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Av., Saint Louis, MO, 63110, USA.
J Mol Biol. 1998 Aug 21;281(3):523-37. doi: 10.1006/jmbi.1998.1964.
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 A 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.
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着重要作用。该激酶家族的特点是存在两个相邻的SH2结构域，它们通过受体编码的酪氨酸磷酸化基序介导其定位于细胞膜。虽然这两种激酶具有许多结构和功能特征，但Syk更广泛存在的特性表明，这种激酶可能适应更多种类的基序来介导其功能。我们展示了与双磷酸化免疫受体酪氨酸激活基序（ITAM）肽复合的Syk串联SH2结构域的晶体结构。该结构通过多对同晶置换在3.0埃分辨率下解析得到。不对称单元包含六个配体结合蛋白拷贝，揭示了两个SH2结构域相对取向具有惊人的灵活性。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不同，Syk的两个SH2结构域可以作为独立单元发挥作用。Syk的SH2模块的构象灵活性和结构独立性可能为Syk更广泛地参与多种信号转导途径提供了分子基础。
