PDF(Pubmed)
Abstract：
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.
摘要：
心脏兴奋-收缩耦合需要二元结构，通过横小管和交界肌浆网的并置，在Z线附近形成了纳米级微域。二元结构和功能的破坏是患病心肌细胞的共同特征。然而,对心脏发育过程中调节二重组织的机制知之甚少，稳态，和疾病。这里,我们完整地使用邻近蛋白质组学，活的心脏来识别二元体附近富含的蛋白质。在这些蛋白质中，CMYA5是一种研究不足的横纹肌蛋白，与Z线共定位，交界肌浆网蛋白，和成熟心肌细胞的横小管。在心脏发育过程中,与Z线相邻的CMYA5定位先于交界性肌浆网定位或横向小管形成。CMYA5消融破坏二重结构，二重定位在Z线，和交界肌浆网Ca2+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CMYA5将交界肌浆网锚定到Z线，提供了对心肌病发病机理的机制见解。建立二元架构，并调节二重Ca2+的释放。
