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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Crystal structure of the catalytic domain of Haspin, an atypical kinase implicated in chromatin organization
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Crystal structure of the catalytic domain of Haspin, an atypical kinase implicated in chromatin organization

机译：Haspin催化结构域的晶体结构，Haspin是一种与染色质组织有关的非典型激酶

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摘要

Haspin, a nuclear and chromosome-associated serine/threonine (S/T) kinase, is responsible for mitotic phosphorylation of Thr-3 of histone H3. Haspin bears recognizable similarity to the eukaryotic protein kinase (ePK) fold, but its sequence is highly divergent and there is therefore considerable interest in its structural organization. We report the 2.15-A crystal structure of the kinase domain of human Haspin. The ePK fold of Haspin contains an array of insertions and deletions. The structure illustrates how Haspin escapes the classical activation scheme of most other kinases. The αC helix, which bears a conserved glutamate that is essential for catalysis, adopts its final active conformation within the small lobe of the kinase. It is sandwiched between an α-helical insertion that precedes the kinase domain, and the activation segment, which adopts an unprecedented conformation. The activation segment, which does not contain phos-phorylatable residues, packs against an unusually structured αEF helix. Significantly extruded from the core of the fold, it forms an extensive plateau, hosting several residues implicated in substrate binding. Overall, the structure of the Haspin kinase domain reveals an active conformation that is poised for substrate recognition and phosphorylation in the absence of external regulators.
机译：Haspin是一种核和染色体相关的丝氨酸/苏氨酸（S / T）激酶，负责组蛋白H3 Thr-3的有丝分裂磷酸化。 Haspin与真核蛋白激酶（ePK）折叠具有可识别的相似性，但其序列高度不同，因此对其结构组织非常感兴趣。我们报告了人类Haspin激酶域的2.15-A晶体结构。 Haspin的ePK折叠包含一系列插入和缺失。该结构说明了Haspin如何逃脱大多数其他激酶的经典激活方案。带有保守的谷氨酸盐的αC螺旋是催化必不可少的，它在激酶的小叶内采用了其最终的活性构象。它夹在激酶结构域之前的α螺旋插入片段和采用史无前例的构象的激活片段之间。不含可磷酸化残基的激活片段紧靠结构异常的αEF螺旋排列。从折叠的核心显着突出，它形成了一个宽阔的平台，包含与底物结合有关的几个残基。总体而言，Haspin激酶结构域的结构揭示了一种活性构象，该构象在没有外部调节剂的情况下可用于底物识别和磷酸化。

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  • 作者

    Fabrizio Villa; Paola Capasso; Marcello Tortorici; Federico Forneris; Ario de Marco; Andrea Mattevi; Andrea Musacchio;

  • 作者单位

    Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy;

    Cogentech (Consortium for Genomic Technologies), IFOM-IEO Campus, Via Adamello 16, 1-20139 Milan, Italy;

    Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy;

    Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy;

    Cogentech (Consortium for Genomic Technologies), IFOM-IEO Campus, Via Adamello 16, 1-20139 Milan, Italy;

    Department of Genetics and Microbiology, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy;

    Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy Research Unit of the Italian Institute of Technology at Cogentech, IFOM-IEO Campus, Via Adamello 16, 1-20139 Milan, Italy;

  • 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
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  • 关键词

    centromere; histone H3; mitosis; activation segment; chromosome segregation;

    机译：着丝粒组蛋白H3;有丝分裂激活段;染色体分离;

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