Professor of Internal Medicine and Cardiology, Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
Circ Res. 2010 Mar 19;106(5):880-90. doi: 10.1161/CIRCRESAHA.109.213256. Epub 2010 Jan 21.
The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy.
Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown.
Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens-1. In a yeast 2-hybrid screen for additional binding partners of Myozap we identified myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity. Myozap, in turn, strongly activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a Rho-dependent fashion. Finally, in vivo knockdown of the Myozap ortholog in zebrafish led to severe contractile dysfunction and cardiomyopathy.
Taken together, these findings reveal Myozap as a previously unrecognized component of a Rho-dependent signaling pathway that links the intercalated disc to cardiac gene regulation. Moreover, its subcellular localization and the observation of a severe cardiac phenotype in zebrafish, implicate Myozap in the pathogenesis of cardiomyopathy.
闰盘是一种高度专业化的细胞-细胞接触结构,可确保收缩型心肌细胞的机械和电偶联。最近,闰盘已被认为是心脏疾病的热点,尤其是遗传性心肌病。
鉴于其复杂的结构和功能,我们假设闰盘中仍有一些重要的分子成分尚未被发现。
我们使用生物信息学筛选,发现并克隆了一种以前未被描述的 54 kDa 心脏蛋白,我们将其命名为 Myozap(心肌丰富的紧密连接蛋白-1 相关蛋白)。Myozap 在心脏和肺部中强烈表达。在心脏组织中,它定位于闰盘,直接与桥粒斑蛋白和紧密连接蛋白-1 结合。在酵母 2 杂交筛选 Myozap 的其他结合伴侣时,我们鉴定出肌球蛋白磷酸酶-RhoA 相互作用蛋白(MRIP),它是 Rho 活性的负调节剂。Myozap 反过来通过其 ERM(Ezrin/radixin/moesin)样结构域以 Rho 依赖的方式强烈激活 SRF 依赖性转录。最后,在斑马鱼中敲低 Myozap 的同源物导致严重的收缩功能障碍和心肌病。
综上所述,这些发现揭示了 Myozap 是一种以前未被识别的 Rho 依赖性信号通路的组成部分,该通路将闰盘与心脏基因调控联系起来。此外,它的亚细胞定位和在斑马鱼中观察到的严重心脏表型提示 Myozap 参与了心肌病的发病机制。