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首页> 外文期刊>Journal of Molecular Biology >Structure of the dimeric autoinhibited conformation of DAPK2, a pro-apoptotic protein kinase.
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Structure of the dimeric autoinhibited conformation of DAPK2, a pro-apoptotic protein kinase.

机译：促凋亡蛋白激酶DAPK2的二聚体自抑制构象的结构。

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摘要

The death-associated protein kinase (DAPK) family has been characterized as a group of pro-apoptotic serine/threonine kinases that share specific structural features in their catalytic kinase domain. Two of the DAPK family members, DAPK1 and DAPK2, are calmodulin-dependent protein kinases that are regulated by oligomerization, calmodulin binding, and autophosphorylation. In this study, we have determined the crystal and solution structures of murine DAPK2 in the presence of the autoinhibitory domain, with and without bound nucleotides in the active site. The crystal structure shows dimers of DAPK2 in a conformation that is not permissible for protein substrate binding. Two different conformations were seen in the active site upon the introduction of nucleotide ligands. The monomeric and dimeric forms of DAPK2 were further analyzed for solution structure, and the results indicate that the dimers of DAPK2 are indeed formed through the association of two apposed catalytic domains, as seen in the crystal structure. The structures can be further used to build a model for DAPK2 autophosphorylation and to compare with closely related kinases, of which especially DAPK1 is an actively studied drug target. Our structures also provide a model for both homodimerization and heterodimerization of the catalytic domain between members of the DAPK family. The fingerprint of the DAPK family, the basic loop, plays a central role in the dimerization of the kinase domain.
机译：死亡相关蛋白激酶（DAPK）家族的特征是一组促凋亡的丝氨酸/苏氨酸激酶，它们在其催化激酶结构域中共享特定的结构特征。 DAPK家族成员中的两个DAPK1和DAPK2是钙调蛋白依赖性蛋白激酶，受寡聚，钙调蛋白结合和自磷酸化作用调节。在这项研究中，我们已经确定了在自抑制域的存在下，在活性位点有和没有结合核苷酸的情况下，鼠DAPK2的晶体和溶液结构。晶体结构显示DAPK2的二聚体呈蛋白质底物结合所不允许的构象。引入核苷酸配体后，在活性位点观察到两个不同的构象。进一步分析了DAPK2的单体和二聚体形式的溶液结构，结果表明DAPK2的二聚体确实是通过两个并置的催化域的缔合形成的，如晶体结构所示。该结构可进一步用于建立DAPK2自磷酸化的模型并与密切相关的激酶进行比较，其中特别是DAPK1是积极研究的药物靶标。我们的结构还提供了DAPK家族成员之间催化域均二聚和异二聚的模型。 DAPK家族的指纹（基本环）在激酶结构域的二聚化中起着核心作用。

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