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Structure of LRRK2 in Parkinson's disease and model for microtubule interaction

机译：帕金森氏病和微管互动模型的LRRK2结构

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摘要

Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease(1) and is also linked to its idiopathic form(2). LRRK2 has been proposed to function in membrane trafficking(3) and colocalizes with microtubules(4). Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease, structural information on the enzyme is limited. Here we report the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in situ structure(5). We propose that the conformation of the LRRK2 kinase domain regulates its interactions with microtubules, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin 1 and cytoplasmic dynein 1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.The structure of the catalytic half of LRRK2 and an atomic model of microtubule-associated LRRK2 suggest that the conformation of the kinase controls the association of LRRK2 with microtubules.
机译：富含亮氨酸的重复激酶2（LRRK2）是家族帕金森病（1）中最常见的基因（1），也与其特发性形式（2）相关联。 LRRK2已提出在膜运输（3）中起作用，并用微管（4）分解均匀。尽管LRRK2对理解和治疗帕金森病的根本重要性，但酶的结构信息有限。在这里，我们报告了LRRK2的催化半部的结构，以及使用报告的冷冻电子断层扫描的微管相关LRRK2的原子模型（5）。我们提出，LRRK2激酶结构域的构象调节其与微管的相互作用，具有闭合的微管对微管的闭合化。我们表明，LRRK2的催化量是长丝形成，并阻断基于微管的电动机Kinesin 1和细胞质Dynein1体外的运动性。激酶抑制剂稳定开放构象可缓解这种干扰并减少细胞中LRRK2长丝的形成，而稳定闭合构象的抑制剂则不是。我们的研究结果表明，LRRK2可以作为基于微管的电动机的障碍，并且对治疗性LRRK2激酶抑制剂的设计具有影响。LRRK2的催化半部的结构和微管相关LRRK2的原子模型表明了激酶对LRRK2与微管的关联进行控制。

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  • 来源
    《Nature》 |2020年第7837期|344-349|共6页
  • 作者

    Deniston C. K.; Salogiannis J.; Mathea S.; Snead D. M.; Lahiri I.; Matyszewski M.; Donosa O.; Watanabe R.; Bohning J.; Shiau A. K.; Knapp S.; Villa E.; Reck-Peterson S. L.; Leschziner A. E.;

  • 作者单位

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA|Novartis Res Fdn Genom Inst La Jolla CA USA;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA|Howard Hughes Med Inst Chevy Chase MD 20815 USA;

    Goethe Univ Inst Pharmaceut Chem Frankfurt Germany;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA|Indian Inst Sci Educ & Res Mohali Dept Biol Sci Mohali India;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA;

    Howard Hughes Med Inst Chevy Chase MD 20815 USA;

    Univ Calif San Diego Mol Biol Sect Div Biol Sci La Jolla CA 92093 USA|La Jolla Inst Immunol La Jolla CA USA;

    Univ Calif San Diego Mol Biol Sect Div Biol Sci La Jolla CA 92093 USA|Univ Oxford Sir William Dunn Sch Pathol Oxford England;

    Ludwig Inst Canc Res Small Mol Discovery Program La Jolla CA USA|Univ Calif San Diego Cell & Dev Biol Sect Div Biol Sci La Jolla CA 92093 USA;

    Goethe Univ Inst Pharmaceut Chem Frankfurt Germany;

    Univ Calif San Diego Mol Biol Sect Div Biol Sci La Jolla CA 92093 USA;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA|Howard Hughes Med Inst Chevy Chase MD 20815 USA|Univ Calif San Diego Cell & Dev Biol Sect Div Biol Sci La Jolla CA 92093 USA;

    Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA|Univ Calif San Diego Mol Biol Sect Div Biol Sci La Jolla CA 92093 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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