...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure and functional characterization of the atypical human kinase haspin
【24h】

Structure and functional characterization of the atypical human kinase haspin

机译：非典型人激酶haspin的结构和功能表征

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The protein kinase haspin/Gsg2 plays an important role in mitosis, where it specifically phosphorylates Thr-3 in histone H3 (H3T3). Its protein sequence is only weakly homologous to other protein kinases and lacks the highly conserved motifs normally required for kinase activity. Here we report structures of human haspin in complex with ATP and the inhibitor iodotubercidin. These structures reveal a constitutively active kinase conformation, stabilized by haspin-specific inserts. Haspin also has a highly atypical activation segment well adapted for specific recognition of the basic histone tail. Despite the lack of a DFG motif, ATP binding to haspin is similar to that in classical kinases; however, the ATP y-phosphate forms hydrogen bonds with the conserved catalytic loop residues Asp-649 and His-651, and a His651Ala haspin mutant is inactive, suggesting a direct role for the catalytic loop in ATP recognition. Enzyme kinetic data show that haspin phosphorylates substrate peptides through a rapid equilibrium random mechanism. A detailed analysis of histone modifications in the neighborhood of H3T3 reveals that increasing methylation at Lys-4 (H3K4) strongly decreases substrate recognition, suggesting a key role of H3K4 methylation in the regulation of haspin activity.
机译：蛋白激酶haspin / Gsg2在有丝分裂中起重要作用，在该蛋白中磷酸化组蛋白H3（H3T3）中的Thr-3。它的蛋白质序列仅与其他蛋白质激酶弱同源，并且缺乏通常激酶活性所需的高度保守的基序。在这里，我们报告与ATP和抑制剂iodotubercidin复合的人haspin结构。这些结构揭示了由haspin特异性插入物稳定的组成型活性激酶构象。 Haspin还具有高度非典型的激活部分，非常适合基本组蛋白尾巴的特异性识别。尽管缺少DFG基序，但ATP与haspin的结合与经典激酶相似。然而，ATPγ-磷酸与保守的催化环残基Asp-649和His-651形成氢键，而His651Ala haspin突变体没有活性，表明催化环在ATP识别中具有直接作用。酶动力学数据表明，哈斯平通过快速平衡随机机制使底物肽磷酸化。对H3T3附近的组蛋白修饰的详细分析表明，Lys-4（H3K4）处甲基化的增加会大大降低底物的识别，表明H3K4甲基化在调节haspin活性中的关键作用。

著录项

  • 来源
  • 作者

    Jeyanthy Eswaran; Debasis Patnaik; Panagis Filippakopoulos; Fangwei Wang; Ross L. Stein; James W. Murray; Jonathan M. G. Higgins; Stefan Knapp;

  • 作者单位

    Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;

    Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;

    Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Partners Center for Drug Discovery and Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital, Harvard NeuroDiscovery Center, Cambridge, MA 02139;

    Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom;

    Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom Department of Clinical Pharmacology, University of Oxford, Oxford OX3 7DQ, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    ATP binding; histone modification; phosphorylation mechanism; germ cell-specific gene 2 (Gsg2); mitosis;

    机译：ATP结合;组蛋白修饰;磷酸化机制生殖细胞特异性基因2（Gsg2）;有丝分裂;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号