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心肌节段弛豫时天然肌球蛋白丝的结构。

Structure of the native myosin filament in the relaxed cardiac sarcomere.

机构信息

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

Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, UK.

出版信息

Nature. 2023 Nov;623(7988):863-871. doi: 10.1038/s41586-023-06690-5. Epub 2023 Nov 1.

DOI:10.1038/s41586-023-06690-5
PMID:37914933
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10665186/
Abstract

The thick filament is a key component of sarcomeres, the basic units of striated muscle. Alterations in thick filament proteins are associated with familial hypertrophic cardiomyopathy and other heart and muscle diseases. Despite the central importance of the thick filament, its molecular organization remains unclear. Here we present the molecular architecture of native cardiac sarcomeres in the relaxed state, determined by cryo-electron tomography. Our reconstruction of the thick filament reveals the three-dimensional organization of myosin, titin and myosin-binding protein C (MyBP-C). The arrangement of myosin molecules is dependent on their position along the filament, suggesting specialized capacities in terms of strain susceptibility and force generation. Three pairs of titin-α and titin-β chains run axially along the filament, intertwining with myosin tails and probably orchestrating the length-dependent activation of the sarcomere. Notably, whereas the three titin-α chains run along the entire length of the thick filament, titin-β chains do not. The structure also demonstrates that MyBP-C bridges thin and thick filaments, with its carboxy-terminal region binding to the myosin tails and directly stabilizing the OFF state of the myosin heads in an unforeseen manner. These results provide a foundation for future research investigating muscle disorders involving sarcomeric components.

摘要

肌球蛋白纤维是肌节的主要组成部分，肌节是横纹肌的基本单位。肌球蛋白纤维蛋白的改变与家族性肥厚型心肌病和其他心脏及肌肉疾病有关。尽管肌球蛋白纤维在心脏中的重要性不言而喻，但它的分子结构仍不清楚。本文通过冷冻电镜断层扫描技术，呈现了松弛状态下天然心肌肌节的分子结构。我们的重建结果揭示了肌球蛋白、titin 和肌球蛋白结合蛋白 C（MyBP-C）在厚纤维中的三维结构。肌球蛋白分子的排列取决于它们在纤维上的位置，这表明它们在应变敏感性和产生力方面具有特殊的能力。三对 titin-α 和 titin-β 链沿纤维轴向排列，与肌球蛋白尾部交织在一起，可能协调着肌节的长度依赖性激活。值得注意的是，虽然三条 titin-α 链沿厚纤维的全长延伸，但 titin-β 链并非如此。该结构还表明，MyBP-C 桥接细肌丝和粗肌丝，其羧基末端区域与肌球蛋白尾部结合，并以一种意想不到的方式直接稳定肌球蛋白头部的关闭状态。这些结果为未来研究涉及肌节成分的肌肉疾病提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/854c964c5935/41586_2023_6690_Fig16_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/62b3e1420cc9/41586_2023_6690_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/572d63489664/41586_2023_6690_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/b5345263962d/41586_2023_6690_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/5b46ed9aca90/41586_2023_6690_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/1eddec35f03e/41586_2023_6690_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/ac4dc4e28876/41586_2023_6690_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/4fa9fcb2fae3/41586_2023_6690_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73c7/10665186/4007bb6b6931/41586_2023_6690_Fig15_ESM.jpg
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