Department of Medicine, University of California San Diego, La Jolla, 92093, USA.
Circ Res. 2010 Aug 6;107(3):348-56. doi: 10.1161/CIRCRESAHA.110.218735. Epub 2010 Jun 10.
The Z-line, alternatively termed the Z-band or Z-disc, is a highly ordered structure at the border between 2 sarcomeres. Enigma subfamily proteins (Enigma, Enigma homolog protein, and Cypher) of the PDZ-LIM domain protein family are Z-line proteins. Among the Enigma subfamily, Cypher has been demonstrated to play a pivotal role in the structure and function of striated muscle, whereas the role of Enigma homolog protein (ENH) in muscle remains largely unknown.
We studied the role of Enigma homolog protein in the heart using global and cardiac-specific ENH knockout mouse models.
We identified new exons and splice isoforms for ENH in the mouse heart. Impaired cardiac contraction and dilated cardiomyopathy were observed in ENH null mice. Mice with cardiac specific ENH deletion developed a similar dilated cardiomyopathy. Like Cypher, ENH interacted with Calsarcin-1, another Z-line protein. Moreover, biochemical studies showed that ENH, Cypher short isoform and Calsarcin-1 are within the same protein complex at the Z-line. Cypher short isoform and Calsarcin-1 proteins are specifically downregulated in ENH null hearts.
We have identified an ENH-CypherS-Calsarcin protein complex at the Z-line. Ablation of ENH leads to destabilization of this protein complex and dilated cardiomyopathy.
Z 线，也称为 Z 带或 Z 盘，是 2 个肌节边界处的高度有序结构。PDZ-LIM 结构域蛋白家族的 Enigma 亚家族蛋白（Enigma、Enigma 同源蛋白和 Cypher）是 Z 线蛋白。在 Enigma 亚家族中，Cypher 已被证明在横纹肌的结构和功能中发挥关键作用，而 Enigma 同源蛋白（ENH）在肌肉中的作用在很大程度上尚不清楚。
我们使用全局和心脏特异性 ENH 敲除小鼠模型研究 Enigma 同源蛋白在心脏中的作用。
我们在小鼠心脏中鉴定了新的 ENH 外显子和剪接异构体。ENH 缺失小鼠表现出心脏收缩受损和扩张型心肌病。心脏特异性 ENH 缺失的小鼠也发展出类似的扩张型心肌病。与 Cypher 一样，ENH 与另一种 Z 线蛋白 Calsarcin-1 相互作用。此外，生化研究表明，ENH、Cypher 短型异构体和 Calsarcin-1 位于 Z 线的同一蛋白复合物中。Cypher 短型异构体和 Calsarcin-1 蛋白在 ENH 缺失心脏中特异性下调。
我们在 Z 线上鉴定了一个 ENH-CypherS-Calsarcin 蛋白复合物。ENH 的缺失导致该蛋白复合物的不稳定和扩张型心肌病。
