CMYA5 establishes cardiac dyad architecture and positioning.
CMYA5 establishes cardiac dyad architecture and positioning.
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DOI：
10.1038/s41467-022-29902-4
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发表时间：
2022-04-21
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
心脏兴奋-收缩偶联需要二联体，即通过横小管和连接肌浆网并置在Z线附近形成的纳米级微区。二分体结构和功能的破坏是患病心肌细胞的共同特征。然而，很少有人知道的机制，调节二分体组织在心脏发育，稳态和疾病。在这里，我们使用邻近蛋白质组学在完整的，活着的心脏，以确定蛋白质富集附近的二分体。在这些蛋白质中，CMYA 5是一种研究不足的横纹肌蛋白，与成熟心肌细胞中的Z线、连接肌浆网蛋白和横小管共定位。在心脏发育过程中，CMYA 5定位邻近Z线先于连接肌浆网定位或横小管形成。CMYA 5消融破坏了二分体结构、Z线处的二分体定位和连接肌浆网Ca 2+释放，导致心脏功能障碍和无法耐受压力超负荷。这些数据通过证明CMYA 5将连接肌浆网锚定到Z线，建立二分体结构，并调节二分体Ca 2+释放，提供了对心肌病发病机制的机制见解。心肌细胞表现出精致的组织亚细胞特征，使有效和协调的心肌收缩，但很少有人知道它是如何实现的。在这里，作者表明，CMYA 5组织心肌细胞钙释放单位，并将它们与肌节对齐，导致钙释放异常，心脏功能障碍，以及在缺乏时无法耐受压力超负荷。
Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca2+ release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca2+ release. Heart muscle cells exhibit exquisitely organized subcellular features that enable efficient and coordinated heart muscle contraction, but little is known about how it is achieved. Here the authors show that CMYA5 organizes cardiomyocyte calcium release units and aligns them to sarcomeres, leading to abnormal calcium release, cardiac dysfunction, and inability to tolerate pressure overload, when absent.
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影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1083/jcb.201112098
发表时间：
2012-03-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Roux KJ;Kim DI;Raida M;Burke B
通讯作者：
Burke B
影响因子：
10.8
作者：
Reynolds, Julia O.;Chiang, David Y.;Wehrens, Xander H. T.
通讯作者：
Wehrens, Xander H. T.
影响因子：
4.8
作者：
Hiess, Florian;Vallmitjana, Alexander;Chen, S. R. Wayne
通讯作者：
Chen, S. R. Wayne
DOI：
10.1016/j.bbamcr.2011.01.030
发表时间：
2011-05-01
影响因子：
5.1
作者：
Bootman, Martin D.;Smyrnias, Ioannis;Roderick, H. Llewelyn
通讯作者：
Roderick, H. Llewelyn