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Structure of the F-actin-tropomyosin complex

机译：F-肌动蛋白-原肌球蛋白复合物的结构

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摘要

Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections, and multiple variations of myopathies. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin. Although crystal structures for monomeric actin (G-actin) are available, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 A in complex with tropomyosin at a resolution of 6.5 A, determined by electron cryomicro-scopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg~(2+) and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin-tropomyosin with its position in our previously determined F-actin-tropomyosin-myosin structure reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.
机译：丝状肌动蛋白（F-actin）是肌肉细丝的主要蛋白质，肌动蛋白微丝是真核细胞骨架的主要成分。不同肌动蛋白同工型的突变会导致早发型常染色体显性非综合征性听力损失，家族性胸主动脉瘤和解剖，以及肌病的多种变化。在横纹肌纤维中，肌球蛋白运动蛋白与肌动蛋白丝的结合主要受原肌球蛋白和肌钙蛋白的调节。肌钙蛋白还与平滑肌和非肌肉细胞中的F-肌动蛋白结合，并在肌钙蛋白不存在的情况下稳定并调节细丝。尽管可获得单体肌动蛋白（G-肌动蛋白）的晶体结构，但仍缺乏高分辨率的F-肌动蛋白结构，这妨碍了我们对致病突变如何影响细肌细丝和微丝功能的理解。在这里，我们报告了F-肌动蛋白的三维结构，其分辨率为3.7 A，与原肌球蛋白复合物的分辨率为6.5 A，通过电子冷冻显微镜测定。该结构表明D环是有序的，并充当稳定F-肌动蛋白丝的疏水和静电相互作用的中心区域。我们清楚地确定了对应于ADP和Mg〜（2+）的图谱密度，并解释了突出的致病突变体的可能作用。 F-肌动蛋白与G-肌动蛋白的比较揭示了细丝形成过程中的构象变化，并确定了D环为其关键介体。我们还证实带负电荷的原肌球蛋白与F-肌动蛋白上带正电荷的凹槽相互作用。原肌球蛋白在F-肌动蛋白-原肌球蛋白中的位置与其在我们先前确定的F-肌动蛋白-原肌球蛋白-肌球蛋白结构中的位置比较，揭示了肌球蛋白诱导的原肌球蛋白的转变。我们的结果使我们能够了解单个突变在肌动蛋白和原肌球蛋白相关疾病的发生中的作用，并将为靶向开发药物奠定坚实的基础。

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  • 来源
    《Nature》 |2015年第7541期|114-117|共4页
  • 作者

    Julian von der Ecken; Mirco Mueller; William Lehman; Dietmar J. Manstein; Pawel A. Penczek; Stefan Raunser;

  • 作者单位

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany;

    Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany;

    Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, USA;

    Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany;

    Department of Biochemistry and Molecular Biology, The University of Texas, Houston Medical School, Houston, Texas 77030, USA;

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany;

  • 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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